KR102476459B1 - Inhibitors of lysine specific demethylase-1 - Google Patents

Abstract

The present invention relates generally to compositions and methods for treating cancer and neoplastic diseases. Substituted heterocyclic derivative compounds and pharmaceutical compositions comprising the compounds are provided herein. The present compounds and compositions are useful for inhibiting lysine specific demethylase-1. In addition, the compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma.

Description

Inhibitors of lysine-specific demethylase-1 {INHIBITORS OF LYSINE SPECIFIC DEMETHYLASE-1}

cross reference

This application claims priority to US Provisional Patent Application Serial No. 62/046,842, filed September 5, 2014, the entire contents of which are incorporated herein by reference.

There is a need in the art for effective treatment of cancer and neoplastic diseases.

Substituted heterocyclic derivative compounds and pharmaceutical compositions comprising the compounds are provided herein. The present compounds and compositions are useful for inhibiting lysine specific demethylase-1 (LSD-1). In addition, the compounds and compositions are useful for the treatment of cancer, such as prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma. Substituted heterocyclic derivative compounds described herein are based on a central heterocyclic ring system such as pyrazine, 4-azaindole, 4-azaindazole, pyrimidine or pyrazole, and the like. The central heterocyclic ring system is further substituted with a 4-cyanophenyl group and a heterocyclyl group.

One embodiment provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

Z is selected from C-H or N;

R is selected from hydrogen, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkyloxy, or aralkyloxy;

W is -L-G, heterocyclyl, or heteroaryl;

L is an alkylene;

G is —N(R ¹ ) ₂ , heterocyclyl, or heteroaryl;

R ¹ is hydrogen or alkyl.

One embodiment provides a compound having the structure of Formula II, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

W is selected from CH, CF, C-Cl, C-CH ₃ , C-CF ₃ , C-OCH ₃ , C-OCH ₂ CH ₃ , or N;

Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ - G, or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R ² and R ³ combine to form an N-linked heterocyclyl ring system;

R is selected from aryl, halogen, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkyloxy, or aralkyloxy.

One embodiment provides a compound having the structure of Formula III, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ - G, or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R ² and R ³ combine to form an N-linked heterocyclyl ring system;

R is selected from alkoxy, carbocyclylalkyloxy, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkynyl, or carbocyclylalkynyl.

One embodiment provides a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ - G, or -C(O)N(R ² )(R ³ );

X ¹ , X ² , and X ³ are each independently selected from N or CR ⁴ ; provided that at least one of X ¹ , X ² , or X ³ is N;

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R ² and R ³ combine to form an N-linked heterocyclyl ring system;

R ⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

R is aryl, heteroaryl, alkynyl, or cycloalkylalkynylene.

One embodiment provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of Formula III, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of Formula IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a method for regulating gene transcription in a cell, comprising the step of inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (I) do.

One embodiment provides a method for regulating gene transcription in a cell, comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula II do.

One embodiment provides a method for regulating gene transcription in a cell, comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula III do.

One embodiment provides a method for regulating gene transcription in a cell, comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula IV do.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula II, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula III, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula IV, or a pharmaceutically acceptable salt thereof.

reference citation

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

As used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, "agent" includes a plurality of such agents, "cell" includes reference to one or more cells (or a plurality of cells) and equivalents thereof known to those skilled in the art, etc. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of the ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, "about" means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), so that the number or numerical range is between 1% and 15% of the stated number or numerical range. means that it can vary. The term "comprising" (and related terms, e.g., "comprises" or "including" or "having" or "including") is used in other specific embodiments, e.g., of a material described herein. It is not intended to exclude that an embodiment of any composition, composition, method, or process or the like “consists of” or “consists essentially of” the recited features.

Justice

As used in the specification and appended claims, unless specified to the contrary, the following terms have the meanings indicated below.

"Amino" means the -NH ₂ radical.

"Cyano" means a -CN radical.

"Nitro" means -NO ₂ radical.

"Oxa" means -O- radical.

"Oxo" means =O radical.

"Thioxo" means =S radical.

"Imino" means =N-H radical.

"Oximo" means =N-OH radical.

"Hydrazino" means =N-NH ₂ radical.

“Alkyl” means a linear or branched hydrocarbon chain radical consisting exclusively of carbon and hydrogen atoms, having from 1 to 15 carbon atoms and containing no unsaturation (eg, C ₁ -C ₁₅ alkyl). In certain embodiments, an alkyl contains 1 to 13 carbon atoms (eg, C ₁ -C ₁₃ alkyl). In certain embodiments, an alkyl contains 1 to 8 carbon atoms (eg, C ₁ -C ₈ alkyl). In other embodiments, an alkyl contains 1 to 5 carbon atoms (eg, C ₁ -C ₅ alkyl). In other embodiments, an alkyl contains 1 to 4 carbon atoms (eg, C ₁ -C ₄ alkyl). In other embodiments, an alkyl contains 1 to 3 carbon atoms (eg, C ₁ -C ₃ alkyl). In other embodiments, an alkyl contains 1 to 2 carbon atoms (eg, C ₁ -C ₂ alkyl). In other embodiments, an alkyl comprises 1 carbon atom (eg, C ₁ alkyl). In other embodiments, an alkyl contains 5 to 15 carbon atoms (eg, C ₅ -C ₁₅ alkyl). In other embodiments, an alkyl contains 5 to 8 carbon atoms (eg, C ₅ -C ₈ alkyl). In other embodiments, an alkyl contains 2 to 5 carbon atoms (eg, C ₂ -C ₅ alkyl). In other embodiments, an alkyl contains 3 to 5 carbon atoms (eg, C ₃ -C ₅ alkyl). In another embodiment, the alkyl group is methyl, ethyl, 1-propyl ( n -propyl), 1-methylethyl ( iso -propyl), 1-butyl ( n -butyl), 1-methylpropyl ( sec -butyl), 2 -methylpropyl ( iso -butyl), 1,1-dimethylethyl ( tert -butyl), 1-pentyl ( n -pentyl). Alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR ^a , - SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N (R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (Where t is 1 or 2), -S(O) _t OR ^a (Where t is 1 or 2), -S(O) _t R ^a (Where t is 1 or 2) and - S(O) _t N(R ^a ) ₂ , wherein t is 1 or 2, wherein each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) ), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) substituted), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (halogen, hydroxy oxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Alkoxy" means a radical bonded through an oxygen atom of the formula -O-alkyl, wherein alkyl is an alkyl chain as defined above.

"Alkenyl" means a straight or branched hydrocarbon chain radical group consisting exclusively of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkenyl contains 2 to 8 carbon atoms. In other embodiments, alkenyl contains 2 to 4 carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example ethenyl (i.e. vinyl), prop-1-enyl (i.e. allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t R ^a (wherein t is 1 or 2) and -S(O) _t N(R ^a ) ₂ where t is 1 or 2, each R ^a independently being optionally substituted with hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl ), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) substituted), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (halogen, hydroxy oxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Alkynyl" means a straight or branched hydrocarbon chain radical group consisting exclusively of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and having from 2 to 12 carbon atoms. In certain embodiments, alkynyl contains 2 to 8 carbon atoms. In other embodiments, alkynyl contains 2 to 6 carbon atoms. In other embodiments, alkynyl contains 2 to 4 carbon atoms. An alkynyl is attached to the rest of the molecule by a single bond, eg ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O) -R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , - N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (wherein t is 1 or 2), -S(O) _t OR ^a (wherein t is 1 or 2), -S(O) _t R ^a (wherein t is 1 or 2) and -S(O) _t N(R ^a ) ₂ , wherein t is 1 or 2, wherein each R ^a is independently hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl, optionally substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) optionally substituted), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycle yl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Alkylene" or "alkylene chain" means a linear or branched divalent hydrocarbon chain linking the remainder of the molecule to a radical group consisting exclusively of carbon and hydrogen, containing no unsaturation, and having from 1 to 12 carbon atoms; , such as methylene, ethylene, propylene, n -butylene and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon of the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene contains 1 to 8 carbon atoms (eg, C ₁ -C ₈ alkylene). In other embodiments, the alkylene contains 1 to 5 carbon atoms (eg, C ₁ -C ₅ alkylene). In other embodiments, the alkylene contains 1 to 4 carbon atoms (eg, C ₁ -C ₄ alkylene). In another embodiment, the alkylene contains 1 to 3 carbon atoms (eg, C ₁ -C ₃ alkylene). In other embodiments, the alkylene contains 1 to 2 carbon atoms (eg, C ₁ -C ₂ alkylene). In other embodiments, an alkylene contains 1 carbon atom (eg, a C ₁ alkylene). In other embodiments, the alkylene contains 5 to 8 carbon atoms (eg, C ₅ -C ₈ alkylene). In other embodiments, the alkylene contains 2 to 5 carbon atoms (eg, C ₂ -C ₅ alkylene). In another embodiment, the alkylene contains 3 to 5 carbon atoms (eg, C ₃ -C ₅ alkylene). Unless stated otherwise specifically in the specification, the alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ , wherein t is 1 or 2, wherein each R ^a is independently selected from hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl) optionally substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (halogen, hydroxy, methoxy, or trifluoromethyl (optionally substituted with), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), hetero Cyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (halogen , hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Alkynylene" or "alkynylene chain" is a linear or branched chain containing at least one carbon-carbon triple bond and having 2 to 12 carbon atoms, consisting exclusively of carbon and hydrogen, linking the remainder of the molecule to a radical group. Geographic i refers to a hydrocarbon chain. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, alkynylene contains 2 to 8 carbon atoms (eg, C ₂ -C ₈ alkynylene). In other embodiments, alkynylene contains 2 to 5 carbon atoms (eg, C ₂ -C ₅ alkynylene). In other embodiments, alkynylene contains 2 to 4 carbon atoms (eg, C ₂ -C ₄ alkynylene). In other embodiments, alkynylene contains 2 to 3 carbon atoms (eg, C ₂ -C ₃ alkynylene). In other embodiments, alkynylene contains 2 carbon atoms (eg, C ₂ alkylene). In other embodiments, alkynylene contains 5 to 8 carbon atoms (eg, C ₅ -C ₈ alkynylene). In other embodiments, alkynylene contains 3 to 5 carbon atoms (eg, C ₃ -C ₅ alkynylene). Unless specifically stated otherwise in the specification, the alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oxymo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(O)-R ^a , -N(R ^a ) ₂ , -C(O)R ^a , -C(O)OR ^a , -C(O)N(R ^a ) ₂ , -N(R ^a )C(O)OR ^a , -OC(O)-N(R ^a ) ₂ , -N(R ^a )C(O)R ^a , -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -S(O) _t OR ^a (where t is 1 or 2), -S(O) _t R ^a (where t is 1 or 2) and -S(O) _t N(R ^a ) ₂ , wherein t is 1 or 2, wherein each R ^a is independently selected from hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl) optionally substituted), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (halogen, hydroxy, methoxy, or trifluoromethyl (optionally substituted with), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), hetero Cyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (halogen , hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

"Aryl" means a radical derived from an aromatic monocyclic or polycyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. Aromatic monocyclic or polycyclic hydrocarbon ring systems contain only hydrogen and carbon of 5 to 18 carbon atoms, wherein at least one ring of the ring system is completely unsaturated, i.e. it is cyclic according to Huckel theory. , delocalized (4n+2) π-electron system. Ring systems from which these aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indan, indene, tetralin, and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (eg, in "aralkyl") refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro , optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , - R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a where t is 1 or 2, -R ^b -S(O) _t R ^a where t is 1 or 2, -R ^b -S(O) _t OR ^a where t is 1 or 2 and -R ^b -S(O) _t N(R ^a ) ₂ (wherein t is 1 or 2), wherein each R ^a is independently selected from hydrogen, alkyl (halogen, hydroxy, methoxy , or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) substituted), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl ), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or hetero arylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a linear or branched alkylene or alkenylene chain, and R ^c is a linear or branched alkylene or alkenylene chain, and unless otherwise indicated, each of the above substituents is unsubstituted.

"Aralkyl" means a radical of the formula -R ^c -aryl, where R ^c is an alkylene chain as defined above, eg methylene, ethylene, and the like. The alkylene chain portion of the aralkyl radical is optionally substituted as defined above for an alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as defined above for aryl groups.

"Aralkenyl" means a radical of the formula -R ^d -aryl, wherein R ^d is an alkenylene chain as defined above. The aryl portion of the aralkenyl radical is optionally substituted as defined above for aryl groups. The alkenylene chain portion of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

"Aralkynyl" means a radical of the formula -R ^e -aryl, wherein R ^e is an alkynylene chain as defined above. The aryl portion of the aralkynyl radical is optionally substituted as defined above for aryl groups. The alkynylene chain portion of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

"Aralkoxy" means a radical bonded through an oxygen atom of the formula -OR ^c -aryl, where R ^c is an alkylene chain as defined above, eg methylene, ethylene, and the like. The alkylene chain portion of the aralkyl radical is optionally substituted as defined above for an alkylene chain. The aryl portion of the aralkyl radical is optionally substituted as defined above for aryl groups.

"Carbocyclyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting exclusively of carbon and hydrogen atoms, containing fused or bridged ring systems, and having from 3 to 15 carbon atoms. In certain embodiments, a carbocyclyl contains 3 to 10 carbon atoms. In other embodiments, carbocyclyl contains 5 to 7 carbon atoms. A carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyls can be saturated (ie, contain only single C-C bonds) or unsaturated (ie, contain one or more double or triple bonds). A fully saturated carbocyclyl radical is also referred to as a "cycloalkyl". Examples of monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unsaturated carbocyclyls are also referred to as “cycloalkenyls”. Examples of monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals are, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2 .1] heptanyl and the like. Unless stated otherwise specifically in the specification, the term "carbocyclyl" refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted ar Alkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hetero Aryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N (R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O )R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2 ), -R ^b -S (O) _t OR ^a (where t is 1 or 2) and -R ^b -S (O) _t N (R ^a ) ₂ (where t is 1 or 2) wherein each R ^a is independently hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl, optionally substituted), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl ( optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (halogen, hydroxyl optionally substituted with oxy, methoxy, or trifluoromethyl, each R ^b is independently a direct bond or a linear or branched alkylene or alkenylene chain, and R ^c is a linear or branched alkylene or alkenylene chain. a nylene chain, and unless otherwise indicated, each of the above substituents is unsubstituted.

"Carbocyclylalkyl" means a radical of the formula -R ^c -carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

"Carbocyclylalkynyl" means a radical of the formula -R ^c -carbocyclyl, where R ^c is an alkynylene chain as defined above. The alkynylene chain and carbocyclyl radical are optionally substituted as defined above.

"Carbocyclylalkoxy" means a radical bonded through an oxygen atom of the formula -OR ^c -carbocyclyl, where R ^c is an alkylene chain as defined above. The alkylene chain and carbocyclyl radical are optionally substituted as defined above.

As used herein, “carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties to carboxylic acid residues. Examples of carboxylic acid isomers are

등을 포함하지만 이에 한정되지 않는다.

Including, but not limited to, etc.

"Halo" or "halogen" means a bromo, chloro, fluoro or iodo substituent.

"Fluoroalkyl" means an alkyl radical as defined above, substituted by one or more fluoro radicals as defined above, for example trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl and the like. The alkyl portion of a fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

"Heterocyclyl" means a stable 3 to 18 membered non-aromatic ring radical containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in the specification, a heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. A heteroatom of a heterocyclyl radical may optionally be oxidized. One or more nitrogen atoms, if present, are optionally quaternized. Heterocyclyl radicals are partially or completely saturated. Heterocyclyl can be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals are dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, Imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- Oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tritianyl, tetrahydropyra nyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless specifically stated otherwise in the specification, the term “heterocyclyl” refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted ar Alkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted hetero Aryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N (R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b -C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N(R ^a )C(O )R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a (where t is 1 or 2 ), -R ^b -S (O) _t OR ^a (where t is 1 or 2) and -R ^b -S (O) _t N (R ^a ) ₂ (where t is 1 or 2) wherein each R ^a is independently hydrogen, alkyl (halogen, hydroxy, methoxy, or trifluoromethyl optionally substituted with), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) optionally substituted), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocycle yl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), hetero Cyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl ( optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl, each R ^b is independently a direct bond or a linear or branched alkylene or alkenylene chain, and R ^c is a linear or branched alkyl a len or alkenylene chain, and unless otherwise indicated, each of the above substituents is unsubstituted.

" N -heterocyclyl" or "N-attached heterocyclyl" contains at least one nitrogen and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom of the heterocyclyl radical; means a heterocyclyl radical as defined above. The N -heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such N -heterocyclyl radicals are 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

" C -heterocyclyl" or "C-attached heterocyclyl" contains at least one heteroatom and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom of the heterocyclyl radical. , means a heterocyclyl radical as defined above. The C -heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C -heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like. .

"Heterocyclylalkyl" means a radical of the formula -R ^c -heterocyclyl, where R ^c is an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

"Heterocyclylalkoxy" means a radical bonded through an oxygen atom of the formula -OR ^c -heterocyclyl, where R ^c is an alkylene chain as defined above. When the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl portion of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

"Heteroaryl" means a radical derived from a 3 to 18 membered aromatic ring radical containing 2 to 17 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, a heteroaryl radical may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one ring in the ring system is completely unsaturated, i.e., it is a cyclic ring system according to Hückel's theory. , contains a delocalized (4n+2) π-electron system. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) of the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryl are azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, Benzo[ b ][1,4]dioxepinil, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodi Oxygenyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4 ,6] imidazo [1,2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta [d] pyrimidinyl, 6,7-dihydro-5H-cyclopenta [4,5] thieno [ 2,3-d] pyrimidinyl, 5,6-dihydrobenzo [h] quinazolinyl, 5,6-dihydrobenzo [h] cinnolinyl, 6,7-dihydro-5H-benzo [6 ,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8 ,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10 -Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxa Zolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl- 1H -pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3 ,4-d] pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6, 7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]p Rimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[ 4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidi nyl, thieno[2,3-c]pridinyl, and thiophenyl (ie, thienyl). Unless specifically stated otherwise in the specification, the term “heteroaryl” refers to alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocycle Rylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(O)-R ^a , -R ^b -OC(O)-OR ^a , -R ^b -OC(O)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(O)R ^a , -R ^b -C(O)OR ^a , -R ^b - C(O)N(R ^a ) ₂ , -R ^b -OR ^c -C(O)N(R ^a ) ₂ , -R ^b -N(R ^a )C(O)OR ^a , -R ^b -N (R ^a )C(O)R ^a , -R ^b -N(R ^a )S(O) _t R ^a (where t is 1 or 2), -R ^b -S(O) _t R ^a ( where t is 1 or 2), -R ^b -S(O) _t OR ^a where t is 1 or 2 and -R ^b -S(O) _t N(R ^a ) ₂ where t is 1 or 2), wherein each R ^a is independently hydrogen, alkyl (halogen, hydroxy, optionally substituted with oxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (halogen, hydroxy, methoxy , or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) optionally substituted), heterocyclyl (halogen, hydroxy, methoxy, or trifluoromethyl optionally substituted), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl) , or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a linear or branched alkylene or alkenylene chain, and R ^c is a linear or branched alkylene or alkenylene chain, and unless otherwise indicated, each of said substituents is unsubstituted.

“ N -heteroaryl” means a heteroaryl radical as defined above, containing at least one nitrogen and wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom of the heteroaryl radical. The N -heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

“ C -heteroaryl” means a heteroaryl radical as defined above, wherein the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom of the heteroaryl radical. The C -heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

"Heteroarylalkyl" means a radical of the formula -R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. When heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of a heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

"Heteroarylalkoxy" means a radical bonded through an oxygen atom of the formula -OR ^c -heteroaryl, where R ^c is an alkylene chain as defined above. When heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to an alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl portion of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

The compounds described herein may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms which may be defined as ( R )- or ( S )- in absolute stereochemical terms. can Unless otherwise stated, all stereoisomeric forms of the compounds described herein are intended to be contemplated by this disclosure. Where compounds described herein contain alkene double bonds, unless otherwise specified, such description is intended to include both E and Z geometric isomers (eg, cis or trans). As such, all possible isomers, as well as racemic and optically pure forms thereof, and all tautomeric forms are also intended to be included. The term "geometric isomer" refers to the E or Z geometric isomer (eg, cis or trans) of an alkene double bond. The term “positional isomer” refers to structural isomers around a central ring, eg ortho- , meta- , and para -isomers around a benzene ring.

"Tautomer" means a molecule capable of proton transfer from one atom of a molecule to another atom of the same molecule. Compounds disclosed herein may, in certain embodiments, exist as tautomers. In situations where tautomerism is possible, there will be a chemical equilibrium of tautomers. The exact ratio of tautomers depends on several factors including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

“Optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted and unsubstituted aryl radicals.

"Pharmaceutically acceptable salts" include both acid and base addition salts. Pharmaceutically acceptable salts of any one of the substituted heterocyclic derivative compounds described herein are intended to include any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

A "pharmaceutically acceptable acid addition salt" is one that retains the biological effectiveness and properties of the free base and is not biologically or otherwise undesirable, and which is not biologically or otherwise undesirable, and which is derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, It means a salt formed with hydrofluoric acid, phosphorous acid, etc. Also organic acids such as aliphatic mono- and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like such as acetic acid, trifluoroacetic acid, Formed with propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. salts are included. Thus, examples of salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, tri Fluoroacetate, Propionate, Caprylate, Isobutyrate, Oxalate, Malonate, Succinate, Suberate, Sebacate, Sebacate, Fumarate, Maleate, Mandelate, Benzoate, Chlorobenzoate, Methyl benzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates and the like. Also contemplated are salts of amino acids, such as alginates, gluconates, and galacturonates (see, for example, Berge SM et al., "Pharmaceutical Salts," which are incorporated herein by reference in their entirety). Journal of Pharmaceutical Science,, 66:1-19 (1997)). Acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to form a salt according to methods and techniques familiar to those skilled in the art.

"Pharmaceutically acceptable base addition salt" means a salt that retains the biological effectiveness and properties of the free acid and is not biologically or otherwise undesirable. These salts are prepared from the addition of an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts may be formed with metals or amines such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Salts derived from organic bases include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethyl Amine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N - Dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, N -methylglucamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N - ethylpiperidine, polyamine resins, and the like, but are not limited thereto. See Berge et al., supra.

As used herein, “treatment” or “treating”, or “mitigating” or “improving” are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results, including but not limited to therapeutic benefit and/or prophylactic benefit. "Therapeutic benefit" means eradication or amelioration of the underlying disease being treated. A therapeutic benefit is also achieved by eradication or amelioration of one or more physiological symptoms associated with the underlying disease, such that improvement is observed in a patient even though the patient may still have the underlying disease. For prophylactic benefit, the composition may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even if such a disease may not have been diagnosed.

"Prodrug" is meant to refer to a compound that can be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Accordingly, the term “prodrug” refers to a pharmaceutically acceptable precursor of a biologically active compound. A prodrug may be inactive when administered to a subject, but is converted to an active compound in vivo, for example by hydrolysis. Prodrug compounds often offer the advantages of solubility, tissue compatibility or delayed release in mammalian organisms (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24( Elsevier, Amsterdam]).

A discussion of prodrugs is found in Higuchi, T., et al., "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium Series, Vol. 14], and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference in their entirety.

The term “prodrug” is also intended to include any covalently linked carrier that releases the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the active compounds as described herein can be prepared by modifying a functional group present in the active compound in such a way that the modification is cleaved into the parent active compound by conventional manipulation or in vivo. Prodrugs include compounds in which a hydroxy, amino or mercapto group is bonded to any group and, when the prodrug of the active compound is administered to a mammalian subject, is cleaved to form a free hydroxy, free amino or free mercapto group, respectively. . Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols in the active compound, or amine functional groups, and the like.

Substituted Heterocyclic Derivative Compounds

Substituted heterocyclic derivative compounds that are lysine specific demethylase-1 inhibitors are described herein. These compounds, and compositions comprising these compounds, are useful in the treatment of cancer and neoplastic diseases. The compounds described herein are useful for treating prostate cancer, breast cancer, bladder cancer, lung cancer and/or melanoma, and the like.

One embodiment provides a compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

Z is selected from C-H or N;

R is selected from hydrogen, halogen, aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkyloxy, or aralkyloxy;

W is -L-G, heterocyclyl, or heteroaryl;

L is an alkylene;

G is —N(R ¹ ) ₂ , heterocyclyl, or heteroaryl;

R ¹ is hydrogen or alkyl.

Another embodiment is a compound having structure I wherein R is selected from aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkyloxy, or aralkyloxy, or a pharmaceutically acceptable salt thereof. provides

Another embodiment provides a compound having the structure of Formula I, wherein Z is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein Z is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein X is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein X is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein X is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein X is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein Y is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein Y is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein Y is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein Y is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein X is CH and Y is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein X is CH, Y is CH, and Z is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I wherein X is CH, Y is CH, and Z is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I wherein X is CH, Y is C-CH ₃ and Z is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I wherein X is CH, Y is C-CH ₃ and Z is N, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula I, wherein W is L-G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is heterocyclyl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula I, wherein W is heteroaryl, or a pharmaceutically acceptable salt thereof. Another embodiment has structure I wherein W is LG and L is selected from C ₁ alkylene, C ₁ -C ₂ alkylene, C ₁ -C ₄ alkylene, or C ₂ -C ₅ alkylene. A compound, or a pharmaceutically acceptable salt thereof, is provided. Another embodiment provides a compound having the structure of Formula I wherein W is LG and L is C ₁ alkylene, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is LG and G is heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is LG and G is heteroaryl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is LG and G is -N(R ¹ ) ₂ , or a pharmaceutically acceptable salt thereof. Another embodiment is wherein W is LG, L is selected from C ₁ alkylene, C ₁ -C ₂ alkylene, C ₁ -C ₄ alkylene, or C ₂ -C ₅ alkylene, and G is -N( R ¹ ) ₂ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is LG and G is -NH ₂ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is LG and G is -NH(alkyl), or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein W is LG and G is -N(alkyl) ₂ , or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula I, wherein W is L-G, G is heterocyclyl, and heterocyclyl is nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment has structure I wherein W is L-G, G is heterocyclyl, heterocyclyl is nitrogen-containing heterocyclyl, and nitrogen-containing heterocyclyl is 5- or 6-membered heterocyclyl. A compound, or a pharmaceutically acceptable salt thereof, is provided. Another embodiment provides a compound having the structure of Formula I, wherein W is L-G, G is heterocyclyl, and the heterocyclyl is selected from the formulas:

Another embodiment provides a compound having the structure of Formula I, wherein W is a heterocyclyl, and the heterocyclyl is a nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment is a compound having the structure of Formula I, wherein W is a heterocyclyl, the heterocyclyl is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a 5- or 6-membered heterocyclyl, or a medicament thereof. A scientifically acceptable salt is provided. Another embodiment provides a compound having the structure of Formula I, wherein W is a heterocyclyl, and the heterocyclyl is a nitrogen-containing heterocyclyl selected from the following formulas, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound having the structure of Formula I, wherein G is a nitrogen-containing heterocyclyl, and the heterocyclyl is selected from:

Another embodiment provides a compound having the structure of Formula I, wherein R is an aryl group or a heterocyclyl group, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein R is an aryl group, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula I, wherein the aryl group is an optionally substituted phenyl group, or a pharmaceutically acceptable salt thereof. Another embodiment is that the optionally substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl, or 4-trifluoromethylphenyl. A compound having the structure of Formula I, or a pharmaceutically acceptable salt thereof, is provided.

One embodiment provides a compound having the structure of Formula II, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

W is selected from CH, CF, C-Cl, C-CH ₃ , C-CF ₃ , C-OCH ₃ , C-OCH ₂ CH ₃ , or N;

Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ - G, or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R ² and R ³ combine to form an N-linked heterocyclyl ring system;

R is selected from aryl, halogen, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkyloxy, or aralkyloxy.

Another embodiment provides a compound having the structure of Formula II, wherein X is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein X is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein X is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein X is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Y is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Y is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Y is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Y is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein X is CH and Y is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein W is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein W is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein X is CH and W is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein X is CH and W is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein X is CH, Y is CH, and W is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein X is CH, Y is CH, and W is CH, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula II, wherein Z is -O-CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Z is -OG, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Z is -N(R ¹ )-CH ₂ -G, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula II, wherein Z is -N(R ¹ )-G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Z is -CH ₂ -CH ₂ -G, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula II, wherein Z is -CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Z is -G, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula II, wherein Z is -C(O)N(R ² )(R ³ ), or a pharmaceutically acceptable salt thereof. Another embodiment is a compound having the structure of Formula II, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently selected from hydrogen or alkyl, or a pharmaceutical preparation thereof. Provides an acceptable salt. Another embodiment is a compound having structure II wherein Z is -C(O)N(R ² )(R ³ ) and R ² and R ³ are independently selected from hydrogen, alkyl, or heterocyclyl; or a pharmaceutically acceptable salt thereof.

Another embodiment is a compound having structure II wherein Z is -C(O)N(R ² )(R ³ ) and R ² and R ³ are independently selected from hydrogen, alkyl, or heterocyclylalkyl. , or a pharmaceutically acceptable salt thereof.

Another embodiment is that Z is —C(O)N(R ² )(R ³ ), R ² and R ³ are both alkyl, and R ² and R ³ are bonded to an N-linked heterocyclyl ring system. , or a pharmaceutically acceptable salt thereof. Another embodiment is that Z is -C(O)N(R ² )(R ³ ), R ² and R ³ are both alkyl, and R ² and R ³ are joined to form an N-linked heterocyclyl. and a heterocyclyl group having an optionally substituted piperidinyl, piperidinyl, morpholinyl, or pyrrolidinyl group, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula II wherein Z is -N(R ¹ )-CH ₂ -G and R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein Z is -N(R ¹ )-G and R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula II, wherein Z is -N(R ¹ )-CH ₂ -G and R ¹ is alkyl, or a pharmaceutically acceptable salt thereof. Another embodiment is a compound having the structure of Formula II wherein Z is -N(R ¹ )-CH ₂ -G, R ¹ is alkyl, and alkyl is C ₁ -C ₄ alkyl, or a pharmaceutically acceptable form thereof. salt is provided. Another embodiment provides a compound having the structure of Formula II, wherein Z is -N(R ¹ )-G and R ¹ is alkyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein Z is -N(R ¹ )-G, R ¹ is alkyl, and alkyl is C ₁ -C ₄ alkyl, or a pharmaceutically acceptable salt thereof. do.

Another embodiment provides a compound having the structure of Formula II, wherein G is heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein G is a nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein G is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a 5- or 6-membered heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II, wherein G is heterocyclyl, and the heterocyclyl is selected from the following formulas, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound having the structure of Formula II, wherein G is a nitrogen-containing heterocyclyl, and the heterocyclyl is selected from:

Another embodiment is a compound having the structure of Formula II, wherein G is heterocyclyl, and the heterocyclyl is selected from an optionally substituted piperidinyl, piperidinyl, morpholinyl, or pyrrolidinyl group, or a medicament thereof. A scientifically acceptable salt is provided.

Another embodiment is a compound having the structure II wherein R is selected from aryl, heteroaryl, heterocyclyl, carbocyclyl, alkoxy, cycloalkylalkyloxy, or aralkyloxy, or a pharmaceutically acceptable salt thereof. provides Another embodiment provides a compound having the structure of Formula II, wherein R is aryl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula II wherein R is an aryl, and the aryl group is an optionally substituted phenyl group, or a pharmaceutically acceptable salt thereof. Another embodiment is wherein R is aryl, the aryl group is an optionally substituted phenyl group, and the optionally substituted phenyl group is 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl group phonyl)phenyl, or a compound having a structure of Formula II selected from 4-trifluoromethylphenyl, or a pharmaceutically acceptable salt thereof.

One embodiment provides a compound having the structure of Formula III, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ - G, or -C(O)N(R ² )(R ³ );

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R ² and R ³ combine to form an N-linked heterocyclyl ring system;

R is selected from alkoxy, carbocyclylalkyloxy, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heteroaryl, heterocyclyl, alkynyl, or carbocyclylalkynyl.

Another embodiment provides a compound having the structure of Formula III, wherein X is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein X is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein X is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein X is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Y is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Y is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Y is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Y is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III wherein X is CH and Y is CH, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein Z is -O-CH ₂ -G, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein Z is -O-G, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein Z is -N(R ¹ )-CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III wherein Z is -N(R ¹ )-CH ₂ -G and R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Z is -N(R ¹ )-CH ₂ -G and R ¹ is alkyl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein Z is -N(R ¹ )-G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Z is -N(R ¹ )-G and R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Z is -N(R ¹ )-G and R ¹ is alkyl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein Z is -CH ₂ -CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Z is -CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Z is -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein Z is -C(O)N(R ² )(R ³ ), or a pharmaceutically acceptable salt thereof.

Another embodiment is a compound having the structure of Formula III, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently selected from hydrogen or alkyl, or pharmaceutical preparations thereof. Provides an acceptable salt. Another embodiment is a compound having structure III wherein Z is -C(O)N(R ² )(R ³ ) and R ² and R ³ are independently selected from hydrogen, alkyl, or heterocyclyl; or a pharmaceutically acceptable salt thereof. Another embodiment is a compound having structure III wherein Z is -C(O)N(R ² )(R ³ ) and R ² and R ³ are independently selected from hydrogen, alkyl, or heterocyclylalkyl. , or a pharmaceutically acceptable salt thereof. Another embodiment is a compound having the structure of Formula III, wherein Z is -C(O)N(R ² )(R ³ ) and R ² and R ³ combine to form an N-linked heterocyclyl ring system; or a pharmaceutically acceptable salt thereof. Another embodiment is wherein Z is -C(O)N(R ² )(R ³ ), R ² and R ³ are joined to form an N-linked heterocyclyl ring system, wherein the heterocyclyl is optionally substituted. A compound having a structure of Formula III selected from a piperidinyl, piperidinyl, morpholinyl, or pyrrolidinyl group, or a pharmaceutically acceptable salt thereof. Another embodiment is that Z is —C(O)N(R ² )(R ³ ), R ² and R ³ are both alkyl, and R ² and R ³ are bonded to an N-linked heterocyclyl ring system. , or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein G is heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein G is a nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein G is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a 5- or 6-membered heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein G is a nitrogen containing heterocyclyl, and the heterocyclyl is selected from:

Another embodiment provides a compound having the structure of Formula III, wherein G is a nitrogen containing heterocyclyl, and the heterocyclyl is selected from:

Another embodiment is a compound having the structure of Formula III, wherein G is heterocyclyl, and the heterocyclyl is selected from an optionally substituted piperidinyl, piperidinyl, morpholinyl, or pyrrolidinyl group, or a medicament thereof. A scientifically acceptable salt is provided.

Another embodiment provides a compound having the structure of Formula III wherein R is selected from alkynyl, or carbocyclylalkynyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III wherein R is selected from alkoxy, or carbocyclylalkyloxy, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III wherein R is selected from heteroaryl, or heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III wherein R is selected from carbocyclyl, carbocyclylalkyl, aryl, or aralkyl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound having the structure of Formula III, wherein R is aryl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound having the structure of Formula III, wherein R is aryl, and the aryl group is an optionally substituted phenyl group, or a pharmaceutically acceptable salt thereof. Another embodiment is wherein R is aryl and the aryl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl, or 4-trifluoromethylphenyl. A compound having the structure of Formula III, wherein the selected optionally substituted phenyl group is provided, or a pharmaceutically acceptable salt thereof.

One embodiment provides a compound having the structure of Formula IV, or a pharmaceutically acceptable salt thereof:

In the above formula,

X and Y are each independently selected from CH, CF, C-CH ₃ , or N;

Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G, -OG, -O-CH ₂ - G, or -C(O)N(R ² )(R ³ );

X ¹ , X ² , and X ³ are each independently selected from N or CR ⁴ ; provided that at least one of X ¹ , X ² , or X ³ is N;

G is carbocyclyl, aryl, heterocyclyl or heteroaryl;

R ¹ is hydrogen or alkyl;

R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, or heterocyclylalkyl, or optionally, R ² and R ³ combine to form an N-linked heterocyclyl ring system;

R ⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;

R is aryl, heteroaryl, alkynyl, or cycloalkylalkynylene.

Another embodiment provides a compound of Formula IV, wherein R is aryl, or heteroaryl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound of formula IV, wherein formula IV is represented by formula IVa, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound of formula IV, wherein formula IV is represented by formula IVb, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound of formula IV wherein formula IV is represented by formula IVc: or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound of formula IV wherein formula IV is represented by formula IVd: or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound of Formula IV, wherein Formula IV is represented by Formula IVe, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound of formula IV wherein formula IV is represented by formula IVf, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound of formula IV, wherein formula IV is represented by formula IVg, or a pharmaceutically acceptable salt thereof:

Another embodiment provides a compound of Formula IV, wherein X is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein X is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein X is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV wherein X is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Y is CH, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Y is CF, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Y is C-CH ₃ , or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV wherein Y is N, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein X is CH and Y is CH.

Another embodiment provides a compound of Formula IV, wherein Z is -O-CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Z is -OG, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Z is -N(R ¹ )-CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Z is -N(R ¹ )-G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Z is -CH ₂ -CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Z is -CH ₂ -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein Z is -G, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein Z is -C(O)N(R ² )(R ³ ). Another embodiment relates to a compound of Formula IV, wherein Z is -C(O)N(R ² )(R ³ ), R ² and R ³ are independently selected from hydrogen or alkyl, or a pharmaceutically acceptable salt thereof. to provide. Another embodiment is a compound of Formula IV, wherein Z is -C(O)N(R ² )(R ³ ), and R ² and R ³ are independently selected from heterocyclyl or heterocyclylalkyl, or a pharmaceutical preparation thereof. Provides an acceptable salt. Another embodiment is a compound of Formula IV or a pharmaceutical preparation thereof wherein Z is -C(O)N(R ² )(R ³ ) and R ² and R ³ combine to form an N-linked heterocyclyl ring system. Provides an acceptable salt.

Another embodiment provides a compound of Formula IV, wherein R ¹ is hydrogen, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein R ¹ is alkyl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound of Formula IV, wherein R ⁴ is hydrogen, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein R ⁴ is C ₁ -C ₃ alkoxy, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound of Formula IV, wherein G is heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein G is a nitrogen containing heterocyclyl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen-containing heterocyclyl, and the nitrogen-containing heterocyclyl is a 5- or 6-membered heterocyclyl. Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein G is heterocyclyl and the heterocyclyl is selected from the formulas:

Another embodiment is

인 화학식 IV의 화합물 또는 이의 약제학적으로 허용되는 염을 제공한다. G is

A compound of formula IV, or a pharmaceutically acceptable salt thereof, is provided.

Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen containing heterocyclyl and the heterocyclyl is selected from the formulas:

Another embodiment provides a compound of Formula IV, wherein R is heteroaryl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein R is a monocyclic nitrogen containing heteroaryl, or a pharmaceutically acceptable salt thereof.

Another embodiment provides a compound of Formula IV, wherein R is a bicyclic nitrogen containing heteroaryl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein R is selected from the formulas:

Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein R is selected from the formulas:

Another embodiment provides a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein R is selected from the formulas:

Another embodiment provides a compound of Formula IV, wherein R is aryl, or a pharmaceutically acceptable salt thereof. Another embodiment provides a compound of Formula IV, wherein R is an optionally substituted phenyl group, or a pharmaceutically acceptable salt thereof. Another embodiment is wherein R is an optionally substituted phenyl selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl, or 4-trifluoromethylphenyl A compound of Formula IV, or a pharmaceutically acceptable salt thereof, is provided. Another embodiment is a compound of Formula IV, wherein R is an optionally substituted phenyl group selected from 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl, or 3-chloro-4-methoxyphenyl, or a pharmaceutical use thereof. acceptable salts are provided.

Another embodiment provides a compound of Formula IVc selected from: or a pharmaceutically acceptable salt thereof.

4-[6-(4-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile;

2-fluoro-4-[3-(2-methyl-2H-indazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzonitrile ,

4-[6-(4-aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile;

4-[6-(4-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-6-yl)pyrazin-2-yl]-2-fluorobenzonitrile;

4-[6-(4-aminopiperidin-1-yl)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)pyrazin-2-yl]-2- fluorobenzonitrile,

4-[6-(4-aminopiperidin-1-yl)-3-{3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl}pyrazine -2-yl] -2-fluorobenzonitrile;

4-[6-(4-aminopiperidin-1-yl)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}pyrazin-2-yl]-2 -fluorobenzonitrile,

2-fluoro-4-{6-[4-(methylamino)piperidyl]-3-(1-methylbenzotriazol-5-yl)pyrazin-2-yl}benzenecarbonitrile;

4-{3-[6-(dimethylamino)(3-pyridyl)]-6-[4-(methylamino)piperidyl]pyrazin-2-yl}-2-fluorobenzenecarbonitrile;

4-{3-[2-(dimethylamino)pyrimidin-5-yl]-6-[4-(methylamino)piperidyl]pyrazin-2-yl}-2-fluorobenzenecarbonitrile;

2-fluoro-4-{6-[4-(methylamino)piperidyl]-3-(1-methylpyrazolo[5,4-b]pyridin-5-yl)pyrazin-2-yl}benzene carbonitrile,

4-{6-[4-(dimethylamino)piperidyl]-3-(2-methyl(2H-indazol-5-yl))pyrazin-2-yl}-2-fluorobenzenecarbonitrile;

2-fluoro-4-[3-(6-fluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl ]benzonitrile,

4-[3-(6,7-difluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]- 2-fluorobenzonitrile;

2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile,

2-fluoro-4-[3-[2-(1-hydroxycyclopentyl)ethynyl]-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzonitrile ,

2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-methylbenzimidazol-5-yl)pyrazin-2-yl]benzonitrile;

2-fluoro-4-[3-(3-hydroxy-3-methylbut-1-ynyl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzo nitrile,

2-fluoro-4-[3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazine -2-yl] benzonitrile,

2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile,

4-[3-(1-ethyl-6-fluorobenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]-2-fluoro robenzonitrile,

4-[6-(4-aminopiperidin-1-yl)-3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2- fluorobenzonitrile,

4-[6-(4-aminopiperidin-1-yl)-3-(1-ethyl-6-fluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile ,

4-[6-(4-aminopiperidin-1-yl)-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile;

4-[6-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] -2-fluorobenzonitrile;

4-[6-(4-aminopiperidin-1-yl)-3-(1-ethyl-6,7-difluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro robenzonitrile, or

4-[6-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1-methylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro Robenzonitrile.

In some embodiments, the substituted heterocyclic derivative compounds described herein have structures provided in Table 1.

[Table 1]

In some embodiments, the substituted heterocyclic derivative compounds described herein have structures provided in Table 2.

[Table 2]

Preparation of Substituted Heterocyclic Derivative Compounds

The compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. “Commercially Available Chemicals” means Acros Organics (Pittsburgh, PA, USA), Aldrich Chemical (Milwaukee, Wisconsin, USA), Sigma Chemical and Fluka including), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, UK), BDH Inc. (Toronto, Canada), BioNet ( Bionet (Cornwall, UK), Chemservice Inc. (West Chester, PA, USA), Crescent Chemical Co. (Harpogue, NY, USA), Eastman Organic Chemicals Chemicals), Eastman Kodak Company (Rochester, NY, USA), Fisher Scientific Co. (Pittsburgh, PA, USA), Fisons Chemicals (Leicestershire, UK) ), Frontier Scientific (Logan, Utah, USA), ICN Biomedicals, Inc. (Costa Mesa, CA, USA), Key Organics (Cornwall, UK) , Lancaster Synthesis (Wyndham, NH, USA), Maybridge Chemical Co. Ltd. (Cornwall, UK), Parish Chemical Co. (Utah, USA). Orem), Pfaltz & Bauer, Inc. (Waterbury, Canada), Polyorganix (Houston, Texas, USA), Pierce Chemical Co. (Illinois, USA). Jurokpo AG), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Products, Inc. (New Brunswick, NJ, USA), TCI America ( Portland, Oregon, USA), Trans World Chemicals, Inc. (Rockville, MD, USA), and Wako Chemicals USA, Inc. (Richmond, VA, USA) ) is obtained from standard commercial sources including.

Methods known to those skilled in the art are identified through various reference books and databases. Suitable reference books and articles that describe the synthesis or provide references to texts describing the preparation of reactants useful for the preparation of the compounds described herein include, for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc. ., New York; S. R. Sandler et al., "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983]; Literature [H. O. House, "Modern Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972]; Literature [T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992]; Literature [J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and Structure", 4th Ed., Wiley-Interscience, New York, 1992]. Additional suitable reference books and articles that describe the synthesis or provide references to texts describing the preparation of reactants useful in the preparation of the compounds described herein include, for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527-29074-5; See Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; See "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

Specific and similar reactants are also available through the Index of Known Chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available at most public and university libraries, and online databases (more details). You can access the American Chemical Society, Washington, DC for information). Chemicals that are known but not commercially available in catalogs can be manufactured by custom chemical synthesis companies, and many standard chemical supply companies (eg, those listed above) offer custom synthesis services. References for the preparation and selection of pharmaceutical salts of the substituted heterocyclic derivative compounds described herein include P. H. Stahl & C. G. Wermuth "Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002].

Substituted heterocyclic derivative compounds are prepared by the general synthetic route described below in Schemes 1-6.

Scheme 1

Referring to Scheme 1, compound A is protected through the use of a phenyl sulfonyl group. Compound B is oxidized and chlorinated to produce compound D. For example, chlorination can occur through formation of pyridine N-oxide compound C followed by treatment with a suitable chlorinating agent, for example POCl ₃ . Compound D is converted to compound F via a palladium mediated cross-linking reaction with a suitable binding partner, such as EB(OH) ₂ boronic acid. Compound F is selectively deprotected under basic conditions to form compound G. Alkylation of compound G is carried out with an alkyl halide under basic conditions to form compound K. Subjecting compound K to a palladium-mediated cross-linking reaction with a suitable binding partner, such as the boronic acid LB(OH) ₂ , provides compound M.

Scheme 2

Referring to Scheme 2, compound F is converted to compound Q via a palladium mediated cross-linking reaction with a suitable binding partner, such as boronic acid PB(OH) ₂ . Compound Q is deprotected under basic hydrolysis conditions to form compound R. Alkylation of compound R with an alkyl halide under basic conditions forms compound T.

Scheme 3

Referring to Scheme 3, nucleophilic substitution on the chloride compound U is carried out under basic conditions with a nucleophile, WW'-VH, such as the amine WW'-NH, or the alcohol W-OH, to form compound X. For example, compound U can be treated with DIEA and the amine WW'-NH. Biaryl compound Z is prepared from aryl halide compound X via a palladium mediated cross-linking reaction with a suitable binding partner, such as boronic acid YB(OH) ₂ . Compound Z is converted to compound AA by condensation with N,N -dimethylformamide dimethyl acetal. Compound AB is obtained from compound AA by reduction of the nitro group and ring condensation to form an indole ring system. Alkylation of compound AB is carried out with the alkyl halide AC-X under basic conditions to form compound AD.

Scheme 4

Referring to Scheme 4, compound AF is prepared by bromination of compound AE. Compound AF is selectively reduced by halogen-lithium exchange, eg, using 1 equivalent of n-LiBu followed by aqueous acid quenching. Compound AG is converted to AH using nitriding conditions, eg aqueous HNO ₃ . Compound AI is prepared by chlorination of compound AH. For example, chlorination can occur through the use of phosphoryl chloride. Compound AJ is obtained from selective oxidation of compound AI, for example with iron in acetic acid. Compound AJ is converted to compound AL via a palladium mediated cross-linking reaction with a suitable binding partner, such as the boronic acid AK-B(OH) ₂ . Compound AO is prepared from the aryl halide compound AL via a palladium mediated cross-linking reaction with a suitable binding partner, such as boronic acid AM-B(OH) ₂ . compound Acylation of AO gives compound AP. This can be achieved using acetic anhydride in the presence of pyridine. Compound AQ is obtained from treatment of compound AP with isoamyl nitrite and acetic acid. Compound AQ is hydrolyzed under basic conditions to form compound AR. Alkylation of compound AR is carried out with an alkyl halide AS-C under basic conditions to form compound AT.

Scheme 5

Referring to Scheme 5, compound AW can be prepared using a palladium catalyzed cross-linking reaction of compound AU with a suitable binding partner, such as boronic acid AV-B(OH) ₂ , at a temperature of 100° C. or lower. A nucleophilic substitution reaction of compound AW with amine AX-NH-AX' at 100° C. under basic conditions provides AY. Palladium catalyzed cross-linking reaction of AY with a suitable binding partner, such as boronic acid AZ-B(OH) ₂ , at elevated temperatures below 120° C. gives pyrimidine BA. Alternatively, compound BC is obtained by subjecting compound AY to Sonogashira cross-linking conditions with a terminal alkyne, such as BB-CCH.

Scheme 6

Referring to Scheme 6, compound BE is condensed with mono-substituted hydrazine BF-NHNH ₂ to form compound BG. Compound BG is hydrolyzed under basic conditions to give compound BH. Compound BH is converted to compound BI by Curtius displacement using diphenyl phosphorazidate (DPPA). Alkylation of compound BI under basic conditions with various electrophiles such as alkyl halides, alkyl mesylates, tosylates and the like is carried out to form compound BK. Compound BK is deprotected under acidic conditions to form compound BL.

Scheme 7

Referring to Scheme 7, compound BN is prepared from a nucleophilic substitution reaction of compound BM with amine AX-NH-AX' under basic conditions. Use of a palladium catalyzed cross-linking reaction of compound BN with a suitable binding partner, such as the boronic acid AV-B(OH) ₂ , provides compound BP. Treatment with N-bromosuccinimide (NBS) gives compound BQ. Palladium catalyzed cross-linking of BQ with a suitable binding partner, such as the boronic acid AZ-B(OH) ₂ , affords pyrazine BR. Alternatively, compound BQ (or AY) is subjected to Sonogashira cross-linking conditions with a terminal alkyne, for example, BB-CCH, to obtain compound BS.

In each of the above reaction sequences or schemes, the various substituents may be selected from among the various substituents otherwise taught herein.

pharmaceutical composition

In certain embodiments, substituted heterocyclic derivative compounds as described herein are administered as pure chemicals. In another embodiment, the substituted heterocyclic derivative compounds described herein are described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)) selected on the basis of selected routes of administration and standard pharmaceutical practice (also referred to herein as pharmaceutically suitable (or acceptable) excipients). , also referred to as a physiologically compatible (or acceptable) excipient, or physiologically compatible (or acceptable) carrier).

Accordingly, a pharmaceutical composition comprising at least one substituted heterocyclic derivative compound, or a stereoisomer, pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. provided herein. The carrier(s) (or excipient(s)) are acceptable or suitable provided that the carrier is compatible with the other ingredients of the composition and is not injurious to the recipient (ie, subject) of the composition.

One embodiment provides a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of Formula II or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of Formula III or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

One embodiment provides a pharmaceutical composition comprising a compound of Formula IV or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In certain embodiments, a substituted heterocyclic derivative compound as described by Formulas I, II, III, or IV is substantially pure, which is, for example, a contaminating intermediate or by-product produced in one or more steps of a synthetic process. It contains less than about 5%, or less than about 1%, or less than about 0.1% of other organic small molecules, such as

Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose, or another suitable material that readily dissolves in the digestive tract. Suitable non-toxic solid carriers may be used including, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like (e.g., See Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

Dosage of a composition comprising at least one substituted heterocyclic derivative compound as described herein depends on the patient's (e.g., human) condition, i.e., age of disease, general health condition, age, and the dose determined by those skilled in the medical arts. may be different depending on other factors that will be used to determine .

The pharmaceutical composition may be administered in a manner appropriate to the condition being treated (or prevented) as determined by one skilled in the medical arts. The appropriate dose and appropriate duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, an appropriate dosage and treatment regimen will provide the composition(s) with therapeutic and/or prophylactic benefit (e.g., improved clinical outcomes, e.g., more frequent complete or partial remissions, or longer disease-free periods and and/or overall survival rate, or reduction in symptom severity). Optimal doses can generally be determined using experimental models and/or clinical trials. The optimal dose will depend on the patient's body mass, body weight, or blood volume.

Oral dosages may typically range from about 1.0 mg to about 1000 mg, 1 to 4, or more times per day.

biology

Epigenetics is the study of genetic changes in gene expression caused by mechanisms other than the underlying DNA sequence. Molecular mechanisms that play a role in epigenetic regulation include DNA methylation and chromatin/histone modifications.

Eukaryotic genomes are highly organized within the cell's nucleus. Packing the 3 billion nucleotides of the human genome into a single cell nucleus requires tremendous compression. Chromatin is a complex of DNA and proteins that makes up chromosomes. Histones are the major protein components of chromatin, acting as spools around which DNA is wound. Changes in chromatin structure are influenced by covalent modifications of histone proteins and non-histone binding proteins. Several classes of enzymes are known that can modify histones at various sites.

There are a total of six classes of histones (HI, H2A, H2B, H3, H4, and H5) organized into two groups: core histones (H2A, H2B, H3, and H4) and linker histones (HI and H5). The basic unit of chromatin is the nucleosome, which consists of about 147 DNA base pairs wrapped around a core histone octet composed of two copies of each of the core histones H2A, H2B, H3, and H4.

The basic nucleosome units are then further organized and compacted by the aggregation and folding of nucleosomes to form highly compacted chromatin structures. A wide variety of states of compression are possible, and the density of the chromatin structure changes during the cell cycle, most often being most compressed during the course of cell division.

Chromatin structure plays an important role in regulating gene transcription, which cannot occur efficiently from highly compressed chromatin. Chromatin structure is regulated by a series of post-translational modifications to histone proteins, particularly histones H3 and H4, most commonly within histone tails that extend beyond core nucleosome structures. These modifications are acetylation, methylation, phosphorylation, ribosylation, thermoylation, ubiquitination, citrullination, deimination, and biotinylation. The cores of histones H2A and H3 may also be modified. Histone modifications are essential for various biological processes such as gene regulation, DNA repair, and chromosome compaction.

Histone methylation is one of the most important chromatin marks; They play important roles in transcriptional regulation, DNA-damage response, heterochromatin formation and maintenance, and X chromosome inactivation. Recent findings have also revealed that histone methylation influences the splicing outcome of pre-mRNAs by influencing the recruitment of splicing regulators. Histone methylation includes mono-, di-, and tri-methylation of lysine, and mono-, symmetric di-, and asymmetric di-methylation of arginine. These modifications may be activating or inhibitory marks, depending on the site and degree of methylation.

histone demethylase

“Demethylase” or “protein demethylase” as referred to herein means an enzyme that removes at least one methyl group from a polypeptide. The demethylase contains a JmjC domain and may be a methyl-lysine or methyl-arginine demethylase. Some demethylases act on histones, for example as histone H3 or H4 demethylases. For example, H3 demethylase can demethylate one or more of H3K4, H3K9, H3K27, H3K36 and/or H3K79. Alternatively, H4 demethylase can demethylate histone H4K20. It is known that demethylases can demethylate mono-, di- and/or tri-methylated substrates. In addition, histone demethylases are methylated on core histone substrates, mononucleosome substrates, dinucleosome substrates and/or oligonucleosome substrates, peptide substrates and/or chromatin (e.g., in cell-based assays). can work

The first lysine demethylase discovered was lysine specific demethylase 1 (LSD1/KDM1), which demethylates both mono- and di-methylated H3K4 or H3K9 using flavins as cofactors. A second class of Jumonji C (JmjC) domain-containing histone demethylases was predicted and confirmed when H3K36 demethylase was discovered using a formaldehyde release assay, which was identified as the JmjC domain-containing histone demethylase 1 (JHDM1/KDM2A) was named

More JmjC domain containing proteins were subsequently identified, which can be phylogenetically classified into 7 subfamilies: JHDM1, JHDM2, JHDM3, JMJD2, JARID, PHF2/PHF8, UTX/UTY, and JmjC domain alone.

LSD-1

Lysine specific demethylase 1 (LSD1) is a histone lysine demethylase that specifically demethylates monomethylated and dimethylated histone H3 at K4 and also demethylates histone H3 dimethylated at K9. Although LSDl's main targets appear to be mono- and di-methylated histone lysines, specifically H3K4 and H3K9, LSDl demethylates methylated lysines in non-histone proteins such as p53, E2F1, Dnmtl and STAT3. There is evidence in the literature that it can be done.

LSDl has a significant degree of structural similarity and amino acid identity/homology to polyamine oxidases and monoamine oxidases, all of which (i.e., MAO-A, MAO-B and LSDl) have nitrogen-hydrogen bonds and/or It is a flavin-dependent amine oxidase that catalyzes the oxidation of nitrogen-carbon bonds. LSD1 also contains an N-terminal SWRIM domain. There are two transcript variants of LSD1 generated by alternative splicing.

How to use

In some embodiments, a compound described herein can inhibit LSD1 activity in a biological sample by contacting the biological sample with a substituted heterocyclic compound as described herein. In some embodiments, a substituted heterocyclic compound as described herein can modulate the level of histone-4 lysine-3 methylation in a biological sample. In some embodiments, substituted heterocyclic compounds as described herein can modulate the level of histone-3 lysine-9 methylation in a biological sample.

In some embodiments, a substituted heterocyclic compound as described herein inhibits LSD1 activity to a greater extent than MAO-A and/or MAO-B.

One embodiment provides a method for regulating gene transcription in a cell, comprising the step of inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of formula (I) do.

One embodiment provides a method for regulating gene transcription in a cell, comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula II do.

One embodiment provides a method for regulating gene transcription in a cell, comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula III do.

One embodiment provides a method for regulating gene transcription in a cell, comprising inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula IV do.

treatment method

Methods of modulating demethylation in a cell or subject generally or with respect to one or more specific target genes are described herein. Differentiation by modulating demethylation; multiplication; apoptosis; tumorigenic, leukemia-inducing or other oncogenic transformation events; hair loss; or modulate various cellular functions, including but not limited to componentization.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula I, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula II, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula III, or a pharmaceutically acceptable salt thereof.

One embodiment provides a method of treating cancer in a patient in need thereof, comprising administering to the patient a compound of Formula IV, or a pharmaceutically acceptable salt thereof.

A further embodiment is a method of treating cancer in a subject, wherein the cancer is selected from prostate cancer, breast cancer, bladder cancer, lung cancer or melanoma.

Other embodiments and uses will be apparent to those skilled in the art in view of the present disclosure. The following examples are provided merely as a description of various embodiments and should not be construed as limiting the invention in any way.

Example

I. Chemical Synthesis

Unless otherwise stated, reagents and solvents were used as provided by commercial suppliers. Anhydrous solvent and oven-dried glassware were used for moisture- and/or oxygen-sensitive synthetic transformations. Yield was not optimized. Response times are approximate and not optimized. Unless otherwise noted, column chromatography and thin layer chromatography (TLC) were performed on silica gel. Spectra are given in ppm (δ) and coupling constants J are reported in hertz. For the proton spectrum, the solvent peak was used as a reference peak.

Preparation 1A: 1-(benzenesulfonyl)-6-bromopyrrolo[3,2- b ]pyridine

Aliquot 6-bromo- 1H -pyrrolo[3,2- b ]pyridine (5 g, 25.5 mmol) into a solution of NaH (1.13 g, 28.05 mmol, 60%) in THF (50 mL) at 0 °C. It was added. The reaction mixture was stirred for 15 minutes. Then, a solution of benzenesulfonyl chloride (4.86 g, 25.5 mmol) in THF (40 mL) was added dropwise at 0 °C. The obtained solution was stirred at room temperature for 18 hours. The reaction mixture was quenched by the addition of 50 mL of H ₂ O. The mixture was concentrated and the resulting solution was extracted with EtOAc (3x). The organic layers were combined, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 8.54 g (99%) of the title compound as a beige solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.01 (d, J = 3.79 Hz, 1 H), 7.60 - 7.69 (m, 2 H), 7.71 - 7.81 (m, 1 H), 8.09 - 8.16 ( m, 2 H), 8.22 (d, J = 3.79 Hz, 1 H), 8.45 - 8.51 (m, 1 H), 8.64 (d, J = 2.02 Hz, 1 H). Calcd [M+H] for C ₁₃ H ₉ BrN ₂ O ₂ S, 337, 339; found, 337, 339.

Preparation 1B: 6-Bromo-1-(phenylsulfonyl) -1H -pyrrolo[3,2- b ]pyridine-4-oxide

To a stirred solution of 6-bromo-1-(phenylsulfonyl) -1H -pyrrolo[3,2- b ]pyridine (8.54 g, 25.4 mmol) in DCM (120 mL) was added 3-chloro at 0°C. Roperbenzoic acid (77 wt %, 6.83 g, 30.49 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solution was washed with saturated aqueous NaHCO ₃ (2x). The organics were dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-15%, MeOH:DCM) to yield 6.34 g (71%) of the title compound as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.05 - 7.09 (m, 1 H), 7.64 - 7.71 (m, 2 H), 7.76 - 7.84 (m, 1 H), 8.08 (s, 1 H) , 8.12 - 8.18 (m, 3 H), 8.57 (d, J = 1.26 Hz, 1 H). Calcd [M+H] for C ₁₃ H ₉ BrN ₂ O ₃ S, 354, 356; found, 354, 356.

Preparation 1C: 1-(benzenesulfonyl)-6-bromo-5-chloropyrrolo[3,2- b ]pyridine

A solution of phosphorus oxychloride (1.43 mL, 15.3 mmol) in DCM (8 mL) was dissolved in 6-bromo-1-(phenylsulfonyl)-1 H -pyrrolo[3,2- b ] in DCM (40 mL). To a mixture of pyridine-4-oxide (4.50 g, 12.8 mmol) and triethylamine (2.13 mL, 15.3 mmol) was added dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour and then at room temperature for 3 hours. The mixture was quenched with water (100 mL). The organic layer was separated, washed with a saturated solution of NaHCO ₃ , brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to yield 2.23 g (47%) of the title compound as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.00 (d, J = 3.79 Hz, 1 H), 7.61 - 7.69 (m, 2 H), 7.74 - 7.80 (m, 1 H), 8.14 (d, J = 7.33 Hz, 2 H), 8.31 (d, J = 3.79 Hz, 1 H), 8.65 (s, 1 H). Calcd [M+H] for C ₁₃ H ₈ BrClN ₂ O ₂ S, 373, 375; found, 373, 375.

Preparation 1D: 4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

1-(benzenesulfonyl)-6-bromo-5-chloropyrrolo[3,2- b ]pyridine (2.23 g, 6.04 mmol), Pd(dppf)Cl ₂ (0.25 g) in dioxane (40 mL) , 0.30 mmol) and aqueous sodium carbonate (2.0 M, 10 mL) was added 4-cyanophenylboronic acid (0.98 g, 6.64 mmol). The reaction mixture was stirred and heated to reflux for 30 minutes. The solvent was evaporated. The residue was taken up in water and extracted with DCM (3x). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to yield 1.79 g (75%) of the title compound as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.06 (d, J =3.79 Hz, 1 H), 7.60 - 7.67 (m, 2 H), 7.73 - 7.79 (m, 3 H), 8.01 (d, J = 8.34 Hz, 2 H), 8.12 (d, J = 7.58 Hz, 2 H), 8.31 (s, 1 H), 8.35 (d, J = 3.79 Hz, 1 H). [M+H] calcd for C ₂₀ H ₁₂ ClN ₃ O ₂ S, 394; found value, 394.

Preparation 1E: 4-(5-chloro- 1H -pyrrolo[3,2- b ]pyridin-6-yl)benzonitrile

4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2- b ]pyridin-6-yl]benzonitrile (1.18 g, 3.00 mmol) in MeOH:THF (3:2, 50 mL) To the mixture was added NaOH (2.5 N, 12 mL). The reaction mixture was stirred at room temperature for 15 minutes. The reaction was acidified (2 N HCl) and extracted with DCM (3x). The organics were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was triturated in DCM (20 mL) and filtered to give 580 mg (76%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 6.60 (br. s., 1 H), 7.72 (d, J = 8.34 Hz, 2 H), 7.81 (t, J = 2.91 Hz, 1 H), 7.85 (s, 1 H), 7.95 (d, J = 8.34 Hz, 2 H), 11.68 (br. s., 1 H). [M+H] calcd for C ₁₄ H ₈ ClN ₃ , 254; found value, 254.

Preparation 1F: tert -Butyl(3 S )-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl]pyrrolidine- 1-carboxylate

( R )-N-boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added to 4-(5-chloro- 1H -pyrrolo[3,2- b ]pyridine in DMF (3 mL) -6-yl)benzonitrile (100 mg, 0.33 mmol) and cesium carbonate (214 mg, 0.65 mmol) were added to the mixture. The reaction mixture was stirred overnight at 90 °C. ( R )-N-Boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added and the reaction was stirred at 90 °C for 2 h. DMF was concentrated in vacuo. The residue was incorporated in DCM and the insoluble solids were filtered off. The filtrate was loaded onto a silica column and chromatographed (0-100%, EtOAc: Hexanes) to yield 125 mg (77%) of the title compound as a colorless oil. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.25 - 1.45 (m, 9 H), 1.59 (br. s., 1 H), 1.76 (br. s., 1 H), 2.67 (br. s ., 2 H), 2.89 - 3.05 (m, 1 H), 3.08 - 3.30 (m, 2 H), 4.18 - 4.39 (m, 2 H), 6.63 (d, J = 3.03 Hz, 1 H), 7.75 (d, J = 8.34 Hz, 2 H), 7.87 (d, J = 3.28 Hz, 1 H), 7.97 (d, J = 8.34 Hz, 2 H), 8.21 (d, J = 2.78 Hz, 1 H) . [M+H] calcd for C ₂₄ H ₂₅ ClN ₃ O ₂ , 437; found value, 437.

Preparation 1G: tert -Butyl(3 S )-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl] pyrrolidine-1-carboxylate

tert -butyl(3 S )-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl]p in dioxane (2 mL) 4-Methylphenylboronic acid (4- _{methylphenylboronic} acid ( 50 mg, 0.36 mmol) was added. The reaction mixture was stirred and heated in a microwave at 143° C. for 1 hour. The solvent was evaporated under vacuum. The residue was incorporated in DCM and filtered. The filtrate was chromatographed (0-90%, EtOAc:Hexanes) to yield 90 mg (79%) of the title compound as a beige solid. [M+H] calcd for C ₃₁ H ₃₂ N ₄ O ₂ , 493; found value, 493.

Example 1: 4-[5-(4-methylphenyl)-1-[[(3 R )-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl]benzo nitrile

tert -butyl(3 S )-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl] in DCM (2 mL) To a mixture of methyl]pyrrolidine-1-carboxylate (90 mg, 0.18 mmol) was added TFA (2 mL). The reaction was stirred for 30 min. The solvent was evaporated under vacuum. The residue was chromatographed (0-20%, MeOH:DCM) to give 56 mg (78%) of the TFA salt of the title compound as a beige solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.61 - 1.77 (m, 1 H), 1.84 - 2.01 (m, 1 H), 2.29 (s, 3 H), 2.76 - 3.01 (m, 3 H) , 3.02 - 3.16 (m, 1 H), 3.24 - 3.37 (m, 2 H), 4.29 - 4.49 (m, 2 H), 6.72 (d, J =3.03 Hz, 1 H), 7.05 - 7.14 (m, 2 H), 7.14 - 7.20 (m, 2 H), 7.42 (d, J =8.34 Hz, 2 H), 7.80 (d, J =8.34 Hz, 2 H), 7.91 (br. s., 1 H) , 8.23 (br. s., 1 H), 8.60 - 8.85 (m, 2 H). [M+H] calcd for C ₂₆ H ₂₄ N ₄ , 393; found value, 393.

Example 2: 4-[5-chloro-1-[[(3 R )-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

tert -butyl(3 S )-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl]pyrroly in DCM (3 mL) To a mixture of din-1-carboxylate (50 mg, 0.11 mmol) was added TFA (1 mL). The reaction was stirred for 2 hours. The solvent was evaporated under vacuum. The residue was chromatographed (0-20%, MeOH:DCM) to yield 35 mg (96%) of the TFA salt of the title compound as a yellow glassy solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.56 - 1.71 (m, 1 H), 1.90 (td, J = 12.69, 7.20 Hz, 1 H), 2.72 - 2.93 (m, 3 H), 3.05 - 3.15 (m, 1 H), 3.21 - 3.30 (m, 1 H), 4.32 (dd, J = 7.20, 4.42 Hz, 2 H), 6.66 (d, J = 3.28 Hz, 1 H), 7.74 (d, J = 8.34 Hz, 2 H), 7.90 (d, J = 3.03 Hz, 1 H), 7.99 (d, J = 8.34 Hz, 2 H), 8.24 (s, 1 H), 8.62 (br. s., 2H). [M+H] calcd for C ₁₉ H ₁₇ ClN ₄ , 337; found value, 337.

Preparation 3A: 4-[1-(benzenesulfonyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2- b ]pyridin-6-yl]benzonitrile (300 mg, 0.76 mmol), Pd (dppf) in dioxane (7 mL) To a mixture of Cl ₂ (31 mg, 0.038 mmol) and aqueous sodium carbonate (2.0 M, 1.15 mL, 2.28 mmol) was added 4-methylphenylboronic acid (310 mg, 2.28 mmol). The reaction mixture was stirred and heated in a microwave at 135° C. for 3 hours. The solvent was evaporated under vacuum. The residue was taken up in water and extracted with DCM. The organics were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to yield 260 mg (47%) of the title compound as a beige solid. [M+H] calcd for C ₂₇ H ₁₉ N ₃ O ₂ S, 450; found value, 450.

Preparation 3B: 4-[5-(4-methylphenyl)-1 H -pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

4-[1-(benzenesulfonyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile (260 mg) in MeOH:THF (2:1, 15 mL) , 0.58 mmol) was added NaOH (2.5 N, 3 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction was neutralized with aqueous HCl and the solvent was evaporated. The residue was taken up in water and extracted with DCM. The organics were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM). The relevant fractions were combined and concentrated to give 90 mg (49%) of the title compound as a beige solid. [M+H] calcd for C ₂₁ H ₁₅ N ₃ , 310; found value, 310.

Preparation 3C: tert -Butyl( 3R )-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl] pyrrolidine-1-carboxylate

( S )-N-Boc-3-bromomethylpyrrolidine (137 mg, 0.52 mmol) was dissolved in 4-[5-(4-methylphenyl)-1 H -pyrrolo[3,2 mmol) in DMF (3 mL). - b ]pyridin-6-yl]benzonitrile (80 mg, 0.26 mmol) and cesium carbonate (422 mg, 1.30 mmol). The reaction mixture was stirred overnight at 90 °C. DMF was removed under vacuum. The residue was incorporated in DCM and the insoluble solids were filtered off. The filtrate was loaded onto a silica column and chromatographed (0-10%, MeOH:DCM) to yield 45 mg (35%) of the title compound as a colorless oil. [M+H] calcd for C ₃₁ H ₃₂ N ₄ O ₂ , 493; found value, 493.

Example 3: 4-[5-(4-methylphenyl)-1-[[(3 S )-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl]benzo nitrile

tert -butyl( 3R )-3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl] in ethanol (2 mL) To methyl]pyrrolidine-1-carboxylate (45 mg, 0.09 mmol) was added HCl in dioxane (4 N, 1 mL). The reaction was stirred for 2 hours and the solvent was evaporated. The residue was chromatographed (0-20%, MeOH:DCM) to give 30 mg (84%) of the HCl salt of the title compound as a beige solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.60 - 1.77 (m, 1 H), 1.89 - 2.01 (m, 1 H), 2.32 (s, 3 H), 2.80 - 3.02 (m, 3 H) , 3.24 - 3.37 (m, 2 H), 4.48 (br. s., 2 H), 6.82 (br. s., 1 H), 7.12 - 7.29 (m, 4 H), 7.45 (d, J = 8.34 Hz, 2 H), 7.84 (d, J = 8.08 Hz, 2 H), 8.18 (s, 1 H), 8.63 (s, 1 H), 9.02 (br. s., 1 H), 9.28 (br. s., 1 H). [M+H] calcd for C ₂₆ H ₂₄ N ₄ , 393; found value, 393.

Preparation 4A: tert -Butyl(3 R )-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl]pyrrolidine- 1-carboxylate

The title compound was prepared from ( S )-N-boc-3-bromomethylpyrrolidine in 25% yield and 4-(5-chloro-1 H -pyrrolo[3,2 - b ]pyridin-6-yl)benzonitrile. [M+H] calcd for C ₂₄ H ₂₅ ClN ₃ O ₂ , 437; found value, 437.

Example 4: 4-[5-chloro-1-[[(3 S )-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

Following the procedure for the preparation of Example 3, the title compound was prepared by tert -butyl( 3R )-3-[[5-chloro-6-(4-cyanophenyl)pyrrolo[3,2- b ]pyridine-1 -yl]methyl]pyrrolidine-1-carboxylate as HCl salt in 90% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.56 - 1.71 (m, 1 H), 1.84 - 1.95 (m, 1 H), 2.71 - 2.92 (m, 2 H), 3.04 - 3.23 (m, 3 H), 4.23 - 4.39 (m, 2 H), 6.66 (d, J = 3.28 Hz, 1 H), 7.74 (d, J = 8.59 Hz, 2 H), 7.90 (d, J =3.28 Hz, 1 H) ), 7.99 (d, J = 8.59 Hz, 2 H), 8.24 (s, 1 H), 8.63 (br. s., 1 H), 8.73 (br. s., 1 H). [M+H] calcd for C ₁₉ H ₁₇ ClN ₄ , 337; found value, 337.

Preparation 5A: 4-[1-(benzenesulfonyl)-5-(4-fluorophenyl)pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

4-[1-(benzenesulfonyl)-5-chloropyrrolo[3,2- b ]pyridin-6-yl]benzonitrile (1 g, 2.54 mmol), Pd (dppf) in dioxane (10 mL) To a mixture of Cl ₂ (100 mg, 0.13 mmol) and aqueous sodium carbonate (2.0 M, 3.31 mL, 7.62 mmol) was added 4-fluoro-phenylboronic acid (1.42 g, 10.16 mmol). The reaction mixture was stirred and heated in a microwave at 143 °C for 4 hours. The crude reactant was used in the next step without further purification. [M+H] calcd for C ₂₆ H ₁₆ FN ₃ O ₂ S, 454; found value, 454.

Preparation 5B: 4-[5-(4-fluorophenyl)-1H-pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

To a mixture of crude 4-[1-(benzenesulfonyl)-5-(4-fluorophenyl)pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile (2.54 mmol) in MeOH (10 mL) ) and NaOH (2.5N, 6 mL) were added. The reaction mixture was stirred at room temperature for 5 hours. The reaction was extracted with DCM. The organics were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM). The relevant fractions were combined and concentrated to give 480 mg (60%) of the title compound as a beige solid. [M+H] calcd for C ₂₀ H ₁₂ FN ₃ , 314; found value, 314.

Preparation 5C: tert -butyl(3R)-3-[[6-(4-cyanophenyl)-5-(4-fluorophenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl ]pyrrolidine-1-carboxylate

Following the procedure for Preparation 3C, the title compound was prepared with 4-[5-(4-fluorophenyl)-1 H -pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile and ( R )-N Prepared from -boc-3-bromomethylpyrrolidine in 100% yield. [M+H] calcd for C ₃₀ H ₂₉ FN ₄ O ₂ , 497; found value, 497.

Example 5: 4-[5-(4-fluorophenyl)-1-[[(3S)-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl] benzonitrile

Following the procedure for the preparation of Example 3, the title compound was prepared by tert -butyl N- [3-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridine- Prepared as HCl salt from 1-yl]propyl]carbamate in 14% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.68 - 1.92 (m, 2 H) 1.96 - 2.23 (m, 2 H) 2.99 - 3.18 (m, 1 H) 3.25 - 3.34 (m, 1 H) ) 3.95 (d, J = 7.07 Hz, 1 H) 4.67 (br. s., 2 H) 6.78 (d, J = 3.03 Hz, 1 H) 7.16 (t, J = 8.08 Hz, 2 H) 7.26 - 7.38 (m, 2 H) 7.44 (d, J = 8.34 Hz, 3 H) 7.83 (d, J =8.34 Hz, 2 H) 8.04 (br. s., 1 H) 8.38 (br. s., 1 H) 8.95 - 9.34 (m, 2 H). [M+H] calcd for C ₂₅ H ₂₁ FN ₄ , 397; found value, 397.

Preparation 6A: 4-(3-bromo-6-methyl-5-nitropyridin-2-yl)morpholine

To a mixture of 3-bromo-2-chloro-6-methyl-5-nitropyridine (2.00 g, 8.0 mmol) and morpholine (700 μL, 8.0 mmol) in DCM (20 mL) was added DIEA (1.40 mL, 8.0 mmol). ) was added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated. The residue was chromatographed (0-5%, MeOH:DCM) to yield 2.21 g (92%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.66 (s, 3 H), 3.57 - 3.63 (m, 4 H), 3.70 - 3.75 (m, 4 H), 8.54 (s, 1 H). Calcd for C ₁₀ H ₁₂ BrN ₃ O ₃ , 303, 305; found, 303, 305.

Preparation 6B: 4-(6-methyl-2-morpholin-4-yl-5-nitropyridin-3-yl)benzonitrile

3-Bromo-6-methyl-2-morphylline-5-nitropyridine (2.21 g, 7.34 mmol), Pd(dppf)Cl ₂ (0.31 g, 0.37 mmol) in dioxane (15 mL) and aqueous sodium carbonate ( 2.0 M, 5 mL) was added 4-cyanophenylboronic acid (1.30 g, 8.08 mmol). The reaction mixture was stirred and heated at 110 °C for 1 hour. The solvent was evaporated and the residue was taken in water and extracted with DCM (3x). The organic layers were combined, washed with brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. The residue was chromatographed (0-5%, MeOH:DCM) to yield 2.15 g (90%) of the title compound as a yellow solid. [M+H] calcd for C ₁₇ H ₁₆ N ₄ O ₃ , 325; found value, 325.

Preparation 6C: 4-[6-[( E )-2-(dimethylamino)ethenyl]-2-morpholin-4-yl-5-nitropyridin-3-yl]benzonitrile

N , N -dimethylformamide dimethyl acetal (5.6 mL, 42.8 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes and heated at 100 °C for 3 hours. The solvent was removed in vacuo to yield 2.7 g (99%) of the title compound as a burgundy red solid. The residue was used in the next step without further purification. [M+H] calcd for C ₂₀ H ₂₁ N ₅ O ₃ , 380; found value, 380.

Preparation 6D: 4-(5-morpholin-4-yl-1 H -pyrrolo[3,2- b ]pyridin-6-yl)benzonitrile

4-[6-[( E )-2-(dimethylamino)ethenyl]-2-morpholin-4-yl-5-nitropyridin-3-yl]benzonitrile (2.7 g, 7.14 mmol) in MeOH: Dissolved in DCM (200 mL, 1:10). Pd/C (10 wt %, 330 mg, 0.72 mmol) was added under nitrogen. The nitrogen atmosphere was replaced with hydrogen, and the reaction was stirred at room temperature for 3 hours. The reaction mixture was filtered through Celite and concentrated in vacuo . The residue was chromatographed (0-10%, MeOH:DCM) to give 1.41 g (65%) of the title compound as a beige solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.83 - 2.99 (m, 4 H), 3.47 - 3.62 (m, 4 H), 6.46 (t, J = 2.15 Hz, 1 H), 7.58 (t, J = 2.91 Hz, 1 H), 7.65 (s, 1 H), 7.85 - 7.98 (m, 4 H), 11.25 (br. s., 1 H). [M+H] calcd for C ₁₈ H ₁₆ N ₄ O, 305; found value, 305.

Preparation 6E: tert -Butyl(3 S )-3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2- b ]pyridin-1-yl]methyl] pyrrolidine-1-carboxylate

To a solution of 4-(5-morpholin-4-yl- 1H -pyrrolo[3,2- b ]pyridin-6-yl)benzonitrile (100 mg, 0.33 mmol) in DMF (3 mL) ( R )-N-boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added followed by cesium carbonate (214 mg, 0.65 mmol) and the mixture was stirred at 90° C. overnight. ( R )-N-Boc-3-bromomethylpyrrolidine (96 mg, 0.37 mmol) was added and the reaction was stirred at 90 °C for 2 h. DMF was removed under vacuum. The residue was incorporated in DCM and the insoluble solids were filtered off. The filtrate was loaded onto a silica column and chromatographed (0-100%, EtOAc:Hexanes) to yield 125 mg (77%) of the title compound as a pale yellow oil. [M+H] calcd for C ₂₈ H ₃₃ N ₅ O ₃ , 488; found, 488.

Example 6: 4-[5-morpholin-4-yl-1-[[(3 R )-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl] benzonitrile

tert -butyl(3 S )-3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2- b ]pyridin-1-yl] in ethanol (4 mL) To methyl]pyrrolidine-1-carboxylate (125 mg, 0.26 mmol) was added HCl in dioxane (4 N, 3 mL). The reaction was stirred for 2 hours. The solvent was evaporated under vacuum. The residue was chromatographed (0-20%, MeOH:DCM) to give 71 mg (70%) of the HCl salt of the title compound as a pale yellow solid (HCl salt). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.73 - 2.87 (m, 2 H), 2.86 - 2.97 (m, 4 H), 3.05 - 3.15 (m, 3 H), 3.22 - 3.30 (m, 2 H) H), 3.54 (d, J = 4.55 Hz, 4 H), 4.23 - 4.32 (m, 2 H), 6.49 (d, J = 3.03 Hz, 1 H), 7.70 (d, J = 3.03 Hz, 1 H) ), 7.91 - 7.99 (m, 4 H), 8.01 (s, 1 H), 9.07 (br. s., 1 H). [M+H] calcd for C ₂₃ H ₂₅ N ₅ O, 388; found, 388.

Preparation 7A: tert -Butyl( 3R )-3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2- b ]pyridin-1-yl]methyl] pyrrolidine-1-carboxylate

( S )-N-boc-3-bromomethylpyrrolidine and 4-(5-morpholin-4-yl-1 H -pyrrolo[3,2- b ]pyridin-6-yl)benzonitrile in 58% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.33 (s, 9 H), 1.50 - 1.67 (m, 1 H), 1.67 - 1.88 (m, 1 H), 2.61 - 2.77 (m, 2 H) , 2.90 (br. s., 4 H), 2.95 - 3.23 (m, 3 H), 3.54 (br. s., 4 H), 4.23 (d, J = 7.58 Hz, 2 H), 6.46 (d, J = 2.80 Hz, 1 H), 7.63 (d, J = 2.78 Hz, 1 H), 7.83 - 8.05 (m, 5 H). [M+H] calcd for C ₂₈ H ₃₃ N ₅ O ₃ , 488; found, 488.

Example 7: 4-[5-morpholin-4-yl-1-[[(3 S )-pyrrolidin-3-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl] benzonitrile

tert -butyl( 3R )-3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2- b ]pyridin-1-yl] in ethanol (4 mL) To methyl]pyrrolidine-1-carboxylate (116 mg, 0.19 mmol) was added HCl in dioxane (4 N, 3 mL). The reaction was stirred for 2 hours. The solvent was evaporated in vacuo to yield 81 mg (99%) of the HCl salt of the title compound as a pale yellow solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.53 - 1.73 (m, 1 H), 1.83 - 1.97 (m, 1 H), 2.72 - 2.91 (m, 2 H), 2.92 - 3.03 (m, 4 H), 3.06 - 3.20 (m, 2 H), 3.21 - 3.38 (m, 1 H), 3.48 - 3.59 (m, 4 H), 4.25 - 4.39 (m, 2 H), 6.58 (br. s., 1 H), 7.82 (br. s., 1 H), 7.89 - 8.02 (m, 4 H), 8.22 (br. s., 1 H), 8.98 (br. s., 1 H), 9.25 (br s., 1 H). [M+H] calcd for C ₂₃ H ₂₅ N ₅ O, 388; found, 388.

Preparation 8A: tert -Butyl 3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2- b ]pyridin-1-yl]methyl]-3-fluoro pyrrolidine-1-carboxylate

Following the procedure for Preparation 6E, the title compound was prepared between 1- N -boc-3-bromomethyl-3-fluoro-pyrrolidine and 4-(5-morpholin-4-yl-1 H -pyrrolo[ Prepared from 3,2- b ]pyridin-6-yl)benzonitrile in 79% yield. [M+H] calcd for C ₂₈ H ₃₂ FN ₅ O ₃ , 506; found value, 506.

Example 8: 4-[1-[(3-fluoropyrrolidin-3-yl)methyl]-5-morpholin-4-ylpyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

tert -butyl 3-[[6-(4-cyanophenyl)-5-morpholin-4-ylpyrrolo[3,2- b ]pyridine Prepared from -1-yl]methyl]-3-fluoropyrrolidine-1-carboxylate in 88% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 1.93 - 2.39 (m, 2 H), 2.89 - 3.03 (m, 4 H), 3.21 - 3.34 (m, 2 H), 3.35 - 3.48 (m, 2 H) H), 3.50 - 3.60 (m, 4 H), 4.73 - 4.87 (m, 2 H), 6.60 (d, J = 2.78 Hz, 1 H), 7.68 (br. s., 1 H), 7.87 - 8.02 (m, 4 H), 8.09 (br. s., 1 H), 9.44 (br. s., 1 H), 9.66 (br. s., 1 H). [M+H] calcd for C ₂₃ H ₂₄ FN ₅ O, 406; found value, 406.

Preparation 9A: tert -Butyl 3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl]-3-fluoro pyrrolidine-1-carboxylate

Following the procedure for Preparation 3C, the title compound was prepared between 1- N -boc-3-bromomethyl-3-fluoro-pyrrolidine and 4-[5-(4-methylphenyl) -1H -pyrrolo[3 Prepared from ,2- b ]pyridin-6-yl]benzonitrile in 41% yield. [M+H] calcd for C ₃₁ H ₃₁ FN ₄ O ₂ , 511; found value, 511.

Example 9: 4-[1-[(3-fluoropyrrolidin-3-yl)methyl]-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

tert -butyl 3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridine to prepare the HCl salt of the title compound following the procedure for the preparation of Example 3 Prepared from -1-yl]methyl]-3-fluoropyrrolidine-1-carboxylate in 66% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 2.08 (br. s., 1 H), 2.23 - 2.31 (m, 1 H), 2.32 (s, 3 H), 3.33 (d, J = 5.05 Hz , 4 H), 4.77 - 5.15 (m, 2 H), 6.90 (br. s., 1 H), 7.17 - 7.29 (m, 4 H), 7.43 (d, J = 8.34 Hz, 2 H), 7.84 (d, J = 8.34 Hz, 2 H), 8.13 (br. s., 1 H), 8.65 (br. s., 1 H), 9.67 (br. s., 1 H), 9.98 (br. s ., 1 H). [M+H] calcd for C ₂₆ H ₂₃ FN ₄ , 411; found value, 411.

Preparation 10A: tert -Butyl(2S)-2-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl]mor Folin-4-carboxylate

Tert - butyl( 2R)-2- (bromomethyl)morpholine-4-carboxylate (145 mg, 0.52 mmol) was added to 4-[5-(4-methylphenyl)-1 H -p in DMF (3 mL). It was added to a mixture of rollo[3,2- b ]pyridin-6-yl]benzonitrile (80 mg, 0.26 mmol) and cesium carbonate (422 mg, 1.30 mmol). The reaction mixture was stirred overnight at 90 °C. The insoluble solid was filtered off and the DMF was concentrated in vacuo to yield 282 mg (100%) of the title compound as a brown semi-solid. The residue was used in the next step without further purification. [M+H] calcd for C ₃₁ H ₃₂ N ₄ O ₃ , 509; found value, 509.

Example 10: 4-[5-(4-methylphenyl)-1-[[(2 R )-morpholin-2-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

Following the procedure for the preparation of Example 3, the title compound was prepared by tert -butyl( 2S )-2-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ] Prepared from pyridin-1-yl]methyl]morpholine-4-carboxylate as HCl salt in 36% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 2.20 - 2.40 (m, 3 H) 2.76 (d, J = 11.37 Hz, 1 H) 2.91 (d, J = 12.13 Hz, 1 H) 3.06 - 3.24 (m, 2 H) 3.37 (d, J = 11.87 Hz, 2 H) 3.94 (d, J = 9.60 Hz, 2 H) 4.13 (br. s., 1 H) 4.43 - 4.74 (m, 2 H) 6.84 (br. s., 1 H) 7.14 - 7.34 (m, 4 H) 7.39 - 7.54 (m, 2 H) 7.85 (d, J = 8.34 Hz, 2 H) 8.06 (br. s., 1 H) 8.49 - 8.75 (m, 1 H) 9.25 - 9.67 (m, 2 H). [M+H] calcd for C ₂₆ H ₂₄ N ₄ O, 409; found value, 409.

Preparation 11A: tert -Butyl(2S)-2-[[6-(4-cyanophenyl)-5-(4-fluorophenyl)pyrrolo[3,2- b ]pyridin-1-yl]methyl ]morpholine-4-carboxylate

Following the procedure for Preparation 10A, the title compound was prepared with 4-[5-(4-fluorophenyl)-1 H -pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile and tert- butyl ( 2R from )-2- (bromomethyl)morpholine-4-carboxylate It was prepared in 100% yield. [M+H] calcd for C ₃₀ H ₂₉ FN ₄ O ₃ , 513; found value, 513.

Example 11: 4-[5-(4-fluorophenyl)-1-[[(2 R )-morpholin-2-yl]methyl]pyrrolo[3,2- b ]pyridin-6-yl] benzonitrile

Following the procedure for the preparation of Example 3, the title compound was prepared by tert -butyl(2S)-2-[[6-(4-cyanophenyl)-5-(4-fluorophenyl)pyrrolo[3,2- Prepared as HCl salt from b ]pyridin-1-yl]methyl]morpholine-4-carboxylate in 27% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.71 - 2.81 (m, 1 H) 2.92 (d, J = 11.62 Hz, 1 H) 3.15 (d, J = 13.14 Hz, 1 H) 3.35 (d , J = 12.88 Hz, 1 H) 3.94 (d, J = 9.09 Hz, 2 H) 4.11 (br. s., 1 H) 4.39 - 4.72 (m, 2 H) 6.80 (br. s., 1 H) 7.12 - 7.29 (m, 2 H) 7.29 - 7.53 (m, 4 H) 7.71 - 7.92 (m, 2 H) 7.92 - 8.10 (m, 1 H) 8.45 (br. s., 1 H) 9.13 - 9.55 ( m, 2H). [M+H] calcd for C ₂₅ H ₂₁ FN ₄ O, 413; found value, 413.

Preparation 12A : tert -Butyl N- [3-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl]propyl]carbamate

Following the procedure for Preparation 10A, the title compound was prepared from 4-[5-(4-methylphenyl)-1 H -pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile and tert-butyl N- (3 -bromopropyl)carbamate in 100% yield. [M+H] calcd for C ₂₉ H ₃₀ N ₄ O ₂ , 466; found value, 466.

Example 12: 4-[1-(3-aminopropyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-6-yl]benzonitrile

tert -butyl N-[3-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrrolo[3,2- b ]pyridin-1-yl according to the procedure for the preparation of Example 3 The title compound was prepared as the HCl salt in 20% yield from ]propyl]carbamate. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 2.05 - 2.21 (m, 2 H) 2.32 (s, 3 H) 2.78 (d, J = 5.81 Hz, 2 H) 4.51 (br. s., 2 H) 6.82 (br. s., 2 H) 7.09 - 7.31 (m, 4 H) 7.46 (d, J = 8.34 Hz, 2 H) 7.84 (d, J = 8.34 Hz, 2 H) 7.98 (br. s., 2 H) 8.16 (br. s., 1 H) 8.62 (s, 1 H). [M+H] calcd for C ₂₄ H ₂₂ N ₄ , 366; found value, 366.

Preparation 13A: 3,5-dibromo-6-methylpyridin-2-ol

To a 1-L three-necked reaction flask packed with aluminum foil was added a solution of 2-hydroxy-6-methyl-pyridine (27.4 g, 0.25 mol) in anhydrous acetonitrile (300 mL). NBS (89 g, 0.5 mol) was added portionwise to the mixture over 20 min at 0 °C. Since the suspension is difficult to stir, additional anhydrous acetonitrile (200 ml) is added and stirring is continued at 30° C. for 1.5 h. The suspension was filtered. The filter cake was washed thoroughly with methanol (50 mL x 3) and dried to yield 58.6 g (88%) of the title compound as a white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.90 (s, 1 H), 2.46 (s, 3 H). [M+H] calcd for C ₆ H ₅ Br ₂ NO, 268, 270; found, 268, 270.

Preparation 13B: 3-bromo-6-methylpyridin-2-ol

In a 2-L three-necked reaction flask (flame dried), 3,5-dibromo-6-methylpyridin-2-ol (51.6 g, 193 mmol) in anhydrous THF (500 mL) was stirred at room temperature under N ₂ . Stir. The mixture was cooled to -67 °C. n-BuLi (178 mL, 445 mmol) was added dropwise over 1 hour at a temperature maintained below -60 °C. The mixture was stirred at -60 °C for 1.5 h. Saturated aqueous NH ₄ Cl (100 mL) was added dropwise over 1 hour at a temperature of -65 °C to -40 °C. The reaction mixture was stirred at -40 °C for 15 min, allowed to reach 25 °C and stirred overnight. The mixture was concentrated to remove THF and the aqueous layer was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL x 2), dried over Na ₂ SO ₄ , filtered, concentrated, and purified by column chromatography on silica gel (10-50%, EtOAc:PE) to give the title compound 6.07 g (17%) were obtained as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.94 (s, 1 H), 7.72 (d, J = 7.2 Hz, 1 H), 5.99 (d, J = 7.2 Hz, 1 H), 2.37 (t, J = 8.4 Hz, 3 H). Calcd [M+H] for C ₆ H ₆ BrNO, 189, 191; found, 189, 191.

Preparation 13C: 3-Bromo-6-methyl-5-nitropyridin-2-ol

In a 500-mL round bottom flask, 65% aqueous HNO ₃ was stirred at 0° C. and 3-bromo-6-methylpyridin-2-ol (5.7 g, 30.3 mmol) was introduced dropwise. The reaction mixture was stirred at room temperature for 3.5 hours. The mixture was poured into ice water (200 mL) and the aqueous layer was extracted with EtOAc (300 mL x 2). The combined organic layers were washed with water, brine (200 mL x 2), dried over Na ₂ SO ₄ , filtered, concentrated, and purified by column chromatography on silica gel (25%, EtOAc:PE) to give the title compound 4.7 g (67%) was obtained as an off-white solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.85 (s, 3 H), 8.66 (s, 1 H), 2.86 (s, 1 H). Calcd [M+H] for C ₆ H ₅ BrN ₂ O ₃ , 235, 237; found, 235, 237.

Preparation 13D: 3-Bromo-2-chloro-6-methyl-5-nitropyridine

In a 500-mL single round bottom flask, POCl ₃ (12 g, 78.1 mmol) was added dropwise to 3-bromo-6-methyl-5-nitropyridin-2-ol (4 g, 15.87 mmol). Then, the mixture was stirred under reflux for 7 hours. The reaction mixture was cooled to 30° C., poured into ice water and stirred for 10 minutes. Then, saturated NaHCO ₃ solution (30 mL) was added. The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with water, brine (200 mL x 2), dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound 2.8 g (65%) were obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.55 (s, 1 H), 2.83 (s, 3 H).

Preparation 13E: 5-bromo-6-chloro-2-methylpyridin-3-amine

To a solution of 3-bromo-2-chloro-6-methyl-5-nitropyridine (2.2 g, 8.7 mmol) in EtOH (100 mL) was added Fe (4.8 g, 85.7 mmol) and HOAc (300 mL). . The mixture was stirred at 30 °C for 13 hours. The solids were filtered and the filtrate was concentrated in vacuo to remove EtOH and most of the HOAc. The aqueous residue was extracted with DCM (100 mL x 3). The combined organic layers were washed with water, brine (100 mL x 2), dried over Na ₂ SO ₄ , filtered, and concentrated to give 1.66 g (86%) of the title compound as a brown solid. Calcd [M+H] for C ₆ H ₆ BrClN ₂ , 221, 223; found, 221, 223.

Preparation 13F: 4- (5-amino-2-chloro-6-methylpyridin-3-yl) benzonitrile

To a solution of 5-bromo-6-chloro-2-methylpyridin-3-amine (1.66 g, 7.48 mmol) in dioxane (50 mL) was added 4-cyanophenylboronic acid (1.2 g, 8.97 mmol), Na ₂ CO ₃ (2.5 g, 23.6 mmol), Pd(dppf)Cl ₂ (306 mg, 0.37 mmol) and a few drops of water were added. The mixture was degassed with N ₂ for 5 minutes and heated to 70° C. for 13 hours. The solid was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (15-25%, EtOAc:PE) to yield 1.42 g (79%) of the title compound as a brown solid. [M+H] calcd for C ₁₃ H ₁₀ ClN ₃ , 244; found value, 244.

Preparation 13G: 4-[5-amino-6-methyl-2-(4-methylphenyl)pyridin-3-yl]benzonitrile

To a solution of 4-(5-amino-2-chloro-6-methylpyridin-3-yl)benzonitrile (1.4 g, 5.76 mmol) in dioxane (50 mL) was added 4-(5-amino-2-chloro- Add 6-methylpyridin-3-yl)benzonitrile (1.1 g, 8.15 mmol), Na ₂ CO ₃ (2.2 g, 20.7 mmol), Pd(dppf)Cl ₂ (0.8 g, 1.09 mmol) and a few drops of water. did The mixture was degassed with N ₂ for 5 minutes and heated to 110° C. for 14 hours. The solid was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (15-25%, EtOAc:PE) to yield 1.3 g (76%) of the title compound as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.54 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 6.0 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.02 (d, J = 8.0 Hz, 2 H), 6.96 (s, 1 H), 3.77 (s, 2 H), 2.56 (s, 3 H), 2.30 (s, 3 H). [M+H] calcd for C ₂₀ H ₁₇ N ₃ , 300; found value, 300.

Preparation 13H: N- [5-(4-cyanophenyl)-2-methyl-6-(4-methylphenyl)pyridin-3-yl]acetamide

To a solution of 4-[5-amino-6-methyl-2-(4-methylphenyl)pyridin-3-yl]benzonitrile (1.3 g, 4.35 mmol) in DCM (50 mL) was added pyridine (1.4 mL, 15 mmol) and Ac ₂ O (1.3 mL, 13 mmol) was added. The mixture was stirred at 30 °C for 16 hours. Saturated aqueous sodium bicarbonate solution was added portionwise to the reaction mixture. The reaction mixture was stirred for 10 minutes. The aqueous layer was extracted with DCM (100 mL x 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to give 1.3 g (86%) of the title compound as a yellow oil. [M+H] calcd for C ₂₂ H ₁₉ N ₃ O, 342; found value, 342.

Preparation 13I: 4-[1-acetyl-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile

To a solution of N- [5-(4-cyanophenyl)-2-methyl-6-(4-methylphenyl)pyridin-3-yl]acetamide (1.3 g, 3.81 mmol) in toluene (20 mL) was added -Butyl nitrite (630 mg, 6.1 mmol), Ac ₂ O (1.1 mL, 11.5 mmol) and KOAc (452 mg, 4.6 mmol) were added. The mixture was heated at 80° C. for 2 h and then cooled to room temperature. 10% NaHCO ₃ (150 mL) was added and the mixture was extracted with EtOAc (100 ml x 3). The combined organic layers were washed with water, NaHCO ₃ , brine, dried over Na ₂ SO ₄ , filtered, and concentrated in vacuo to yield 0.8 g (60%) of the title compound as a brown solid. [M+H] calcd for C ₂₂ H ₁₆ N ₄ O, 353; found value, 353.

Preparation 13J: 4-[5-(4-methylphenyl)-1H-pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile

4-[1-acetyl-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile (0.8 g, 2.27 mmol) in THF/MeOH (30 mL, 2:1) NaOH (2.3 M, 3 mL) was added. The resulting mixture was stirred at room temperature for 1 hour. Solvent was removed under vacuum. The residue was taken up in water (30 mL) and the aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with water, brine, dried over Na ₂ SO ₄ and concentrated. The crude product was further purified by column chromatography (33%, EtOAc:PE) to yield 0.41 g (58%) of the title compound as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.29 (s, 1 H), 8.07 (s, 1 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.42 (d, J = 8.0 Hz , 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 2.33 (s, 3 H). [M+H] calcd for C ₂₀ H ₁₄ N ₄ , 311; found, 311.

Preparation 13K: tert -Butyl 3-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-1-yl]methyl]pyrrolidin-1 -Carboxylate

4-[5-(4-methylphenyl) -1H -pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile (100 mg, 0.32 mmol) and tert -butyl 3- in DMF (5 mL) To a solution of [(4-ethylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate (185 mg, 0.52 mmol) was added potassium carbonate (209 mg, 0.96 mmol). The mixture was then stirred overnight at room temperature. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by prep-HPLC to give the title compound 66 mg (43%) were obtained as a white solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.32 (s, 1 H), 7.71 (s, 1 H), 7.57 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 5.6 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 4.41 (d, J = 7.2 Hz, 2 H), 3.48-3.43 (m, 2 H) H), 3.34-3.32(m, 1 H), 3.18(t, J = 4.8 Hz, 1 H), 2.90-2.91(m, 1 H), 2.33(s, 3 H), 2.00-1.98(m, 1 H), 1.75-1.73 (m, 1 H), 1.42 (s, 9 H). [M+H] calcd for C ₃₀ H ₃₁ N ₅ O ₂ , 494; found value, 494.

Example 13: 4-[5-(4-methylphenyl)-1-(pyrrolidin-3-ylmethyl)pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile

A solution of hydrochloric acid (4 M, 3 mL) in dioxane was dissolved in 4-[5-(4-methylphenyl)-1-(pyrrolidin-3-ylmethyl)pyrazolo[4,3- b ]pyridine-6- yl]benzonitrile (66 mg, 0.13 mmol). The mixture was then stirred at room temperature for 30 minutes. The resulting mixture was concentrated to yield 49 mg (94%) of the title compound as a white solid. ¹ H NMR (CD ₃ OD, 400 MHz): δ 9.10 (s, 1 H), 8.54 (s, 1 H), 7.73 (d, J = 8.0 Hz, 2 H), 7.56 (d, J = 8.0 Hz , 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 8.0 Hz, 2 H), 4.87-4.85 (m, 2 H), 3.62-3.49 (m, 3 H) , 3.29-3.17 (m, 2 H), 2.39 (s, 3 H), 2.28-2.24 (m, 1 H), 1.99-1.93 (m, 1 H). [M+H] calcd for C ₂₅ H ₂₃ N ₅ , 394; found value, 394.

Preparation 14A: tert -Butyl 4-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-1-yl]methyl]piperidin-1 -Carboxylate

4-[5-(4-methylphenyl)-1H-pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile (80 mg, 0.26 mmol) and tert -butyl 4-( To a solution of bromomethyl)piperidine-1-carboxylate (138 mg, 0.49 mmol) was added potassium carbonate (120 mg, 0.55 mmol). The mixture was stirred overnight at room temperature. The mixture was diluted with EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with water (20 mL x 2), brine, dried over Na ₂ SO ₄ , filtered, and concentrated to give the title compound as a yellow oil. This oil was used in the next step without further purification. [M+H] calcd for C ₃₁ H ₃₃ N ₅ O ₂ , 508; found value, 508.

Example 14: 4-[5-(4-methylphenyl)-1-(piperidin-4-ylmethyl)pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile

tert -butyl 4-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-1-yl]methyl]piperidine-1-carboxylate ( 76 mg, 0.15 mmol) in dioxane (4 M, 4 mL) was added at 0 °C. The mixture was heated to room temperature and stirred for 30 minutes. The reaction mixture was concentrated and the residue was purified by prep-HPLC to give 25 mg (41%) of the title compound as a white solid. ¹ H NMR (D ₂ O, 400 MHz): δ 8.18(s, 1 H ), 8.06(s, 1 H), 7.45(d, J = 8.4 Hz, 2 H), 7.16(d, J = 8.0 Hz, 2 H), 6.94(s, 4 H), 4.33(d, J = 6.8 Hz, 2 H), 3.31 (d, J = 13.2 Hz, 2 H), 2.83 (t, J = 10.4 Hz, 2 H), 2.24-2.23 (m, 1 H), 2.14 (s, 3 H) , 1.69 (d, J = 11.6 Hz, 2 H), 1.47–1.29 (m, 2 H). calcd for C ₂₆ H ₂₅ N ₅ , 408; found value, 408.

Preparation 15A: tert -butyl( 1S,5R )-6-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-1-yl]methyl ]-3-azabicyclo[3.1.0]hexane-3-carboxylate

4-[5-(4-methylphenyl) -1H -pyrazolo[4,3- b ]pyridin-6-yl]benzonitrile (100 mg, 0.32 mmol) in DMF (8 mL), tert-butyl ( 1S A mixture of ,5R )-6-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (115 mg, 0.49 mmol) and K ₂ CO ₃ (150 mg, 0.69 mmol) was heated to 60 °C. was stirred overnight. The mixture was cooled to room temperature and diluted with water (50 mL) and ethyl acetate (50 mL). The solution was extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water (50 mL x 3), brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by pre-HPLC to yield 62 mg (38%) of the title compound as a white solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.35 (s, 1 H), 7.76 (s, 1 H), 7.61 (d, J = 7.8 Hz, 2 H), 7.36 (d, J = 8.2 Hz, 2 H), 7.21 (d, J = 7.4 Hz, 2 H), 7.09 (d, J = 7.8 Hz, 2 H), 4.41 - 4.35 (m, 2 H), 3.63 - 3.61 (m, 1 H), 3.50 - 3.48 (m, 1 H), 3.37 - 3.36 (m, 2 H), 2.35 (s, 3 H), 1.62 - 1.67 (m, 2 H), 1.40 (s, 9 H), 1.26 - 1.14 ( m, 1 H). [M+H] calcd for C ₃₁ H ₃₁ N ₅ O ₂ , 506; found value, 506.

Example 15: 4-[1-[[( 1S,5R )-3-azabicyclo[3.1.0]hexan-6-yl]methyl]-5-(4-methylphenyl)pyrazolo[4,3-b ]pyridin-6-yl]benzonitrile

tert -butyl( 1S,5R )-6-[[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3- b ]pyridin-1-yl in DCM (5 mL) To a solution of ]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (62 mg, 0.12 mmol) was added hydrochloric acid in dioxane (4 M, 2 mL). The mixture was then stirred at room temperature for 30 minutes. The resulting mixture was concentrated to yield 35 mg (72%) of the title compound as an HCl salt as a yellow oil. ¹ H NMR (CD ₃ OD, 400 MHz): δ 8.85 (s, 1 H), 8.45 (s, 1 H), 7.72 (d, J = 6.9 Hz, 2 H), 7.54 (d, J = 7.4 Hz , 2 H), 7.24 - 7.31 (m, 4 H), 4.64 (d, J = 6.4 Hz, 2 H), 3.61 - 3.59 (m, 4 H), 2.38 (s, 3 H), 2.08 - 2.10 ( m, 2 H), 1.72 - 1.74 (m, 1 H). [M+H] calcd for C ₂₆ H ₂₃ N ₅ , 406; found value, 406.

Preparation 16A: 4- (2,5-dichloropyrimidin-4-yl) benzonitrile

(4-cyanophenyl)boronic acid (1.47 g, 10 mmol), PdCl in a 100 mL pressure vessel charged with 2,4,5-trichloropyrimidine (1.83 g, 10 mmol) in dioxane (20 mL). ₂ (dppf) (146 mg, 0.2 mmol), and Na ₂ CO ₃ (10 mL, 2M) were added. The mixture was purged with N ₂ for 5 minutes and sealed. The reaction was maintained at 70° C. for 1 hour under vigorous stirring. Water was added and the heterogeneous mixture was filtered. The filter cake was incorporated into ethanol, stirred for 10 minutes, filtered, and dried under vacuum to give the title compound (2.2 g, 89%) as off-white crystals. [M+H] calcd for C ₁₁ H ₅ N ₃ Cl ₂ , 250; found value, 250.

Preparation 16B: tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxylate

Into a vial containing 4-(2,5-dichloropyrimidin-4-yl)benzonitrile (496 mg, 2 mmol) in ethanol (5 mL), tert -butyl(3 S )-3-(aminomethyl)p Rolidine-1-carboxylate (400 mg, 2 mmol), and DIEA (694 μl, 4 mmol) were added. The reaction was stirred at 100 °C for 16 hours. The reaction was concentrated in vacuo and the residue was purified by column chromatography (0-50% gradient EtOAc in hexanes) to give the title compound (743 mg, 90%) as a yellow amorphous solid. [M+H] calcd for C ₂₁ H ₂₄ N ₅ O ₂ Cl, 414; found value, 414.

Example 16: 4-[5-(4-methylphenyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1- in dioxane (3 mL) (4-methylphenyl)boronic acid (136 mg, 1 mmol), PdCl ₂ (dppf) (36 mg, 0.05 mmol), and Na ₂ CO ₃ ( 1 mL, 2M) was added. The mixture was purged with N ₂ for 2 min and sealed. The reaction was irradiated in a microwave at 120° C. for 2 hours or held at 120° C. on a heating block for 16 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (0-50% EtOAc in hexane gradient) to give a yellow amorphous foam, which was further prep-HPLC (75% ACN in water with 0.1% HCO ₂ H- 95% gradient) to obtain tert -butyl(3 R )-3-({[4-(4-cyanophenyl)-5-(4-methylphenyl)pyrimidin-2-yl]amino}methyl)pyrroly Dean-1-carboxylate was obtained as a yellow amorphous foam. The foam was dissolved in DCM (2 mL) and then TFA (2 mL) was added dropwise. The reaction was stirred at ambient temperature for 30 min and concentrated in vacuo to give the TFA salt of the title compound (109 mg, 47%) as an off-white amorphous foam. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.79 - 1.95 (m, 1 H), 2.12 - 2.29 (m, 1 H), 2.35 (s, 3 H), 2.78 - 2.93 (m, 1 H), 3.12 - 3.26 (m, 1 H), 3.26 - 3.49 (m, 3 H), 3.49 - 3.61 (m, 1 H), 3.61 - 3.70 (m, 1 H), 5.76 - 6.01 (m, 1 H), 6.88 - 7.02 (m, 2 H), 7.08 - 7.18 (m, 2 H), 7.47 - 7.62 (m, 4 H), 8.09 - 8.29 (m, 1 H), 8.29 - 8.39 (m, 1 H). [M+H] calcd for C ₂₃ H ₂₃ N ₅ , 370; found value, 370.

Example 17: 4-(5-chloro-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl)benzonitrile

tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1 dissolved in DCM (2 mL) - TFA (2 mL) was added dropwise to the carboxylate. The reaction was stirred at ambient temperature for 30 min and concentrated in vacuo to give the TFA salt of the title compound (59 mg, 47%) as an off-white amorphous foam. ¹ H NMR (400 MHz, CDCl ₃ - d ): δ ppm 1.68 - 2.08 (m, 1 H), 2.12 - 2.49 (m, 1 H), 2.66 - 3.11 (m, 1 H), 3.37-3.90 (m , 6 H), 7.67 - 8.13 (m, 4 H), 8.44 - 8.83 (s, 1 H), 9.45 - 10.14 (br. s., 2 H). [M+H] calcd for C ₁₆ H ₁₆ N ₅ Cl, 314; found value, 314.

Example 18: 4-[5-(4-fluorophenyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino } It was prepared using methyl)pyrrolidine-1-carboxylate and (4-fluorophenyl)boronic acid in 34% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.59 - 1.85 (m, 1 H), 1.97 - 2.17 (m, 1 H), 2.59 - 2.72 (m, 1 H), 2.82 - 3.01 (m , 1 H), 3.06 - 3.36 (m, 2 H), 3.37 - 3.50 (m, 2 H), 7.15 (d, J =7.07 Hz, 4 H), 7.40 - 7.56 (m, 2 H), 7.67 - 7.79 (m, 1 H), 7.79 - 7.88 (m, 2 H), 8.38 (s, 1 H), 8.54 - 8.78 (m, 2 H). [M+H] calcd for C ₂₂ H ₂₀ N ₅ F, 374; found value, 374.

Example 19: 4-[5-(4-chlorophenyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino } It was prepared in 31% yield using methyl)pyrrolidine-1-carboxylate, (4-chlorophenyl)boronic acid and pinacol ester. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.62 - 1.83 (m, 1 H), 1.94 - 2.17 (m, 1 H), 2.62 - 2.74 (m, 1 H), 2.86 - 3.02 (m , 1 H), 3.13 (m, 1 H), 3.27 (m, 2 H), 3.43 (m, 2 H), 7.07 - 7.19 (m, 2 H), 7.29 - 7.43 (m, 2 H), 7.44 - 7.56 (m, 2 H), 7.62 - 7.75 (m, 1 H), 7.77 - 7.89 (m, 2 H), 8.40 (s, 1 H), 8.60 (br. s., 1 H). [M+H] calcd for C ₂₂ H ₂₀ N ₅ Cl, 390; found value, 390.

Preparation 20A: tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]oxy}methyl)pyrrolidine-1-carboxylate

NaH (144 mg , 144 mg , 3.6 mmol, 60%) was added. The reaction was allowed to stir at ambient temperature for 30 min before 4-(2,5-dichloropyrimidin-4-yl)benzonitrile (744 mg, 3 mmol) was added at 0°C. The reaction was allowed to heat to ambient temperature and stirred for 16 hours. The reaction was quenched with saturated NH ₄ Cl and incorporated into EtOAc. The organic layer was subsequently washed with water (3X) and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (0-40% gradient of EtOAc in hexanes) to give the title compound (655 mg, 53%) as a yellow amorphous solid. [M+H] calcd for C ₂₁ H ₂₃ N ₄ O ₃ Cl, 415; found value, 415.

Example 20: 4-[5-(4-methylphenyl)-2-[(3 R )-pyrrolidin-3-ylmethoxy]pyrimidin-4-yl]benzonitrile

tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]oxy}methyl)pyrrolidine-1- in dioxane (3 mL) (4-methylphenyl)boronic acid (68 mg, 0.5 mmol), PdCl ₂ (dppf) (36 mg, 0.05 mmol), and Na ₂ CO ₃ ( 1 mL, 2M) was added. The mixture was purged with N ₂ for 2 min and sealed. The reaction was irradiated in a microwave at 120° C. for 2 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (0-40% EtOAc in hexane gradient) to give a yellow amorphous foam, which was further prep-HPLC (gradient 75%-95% ACN in water with 0.1% HCO ₂ H). ) to obtain tert -butyl( 3R )-3-({[4-(4-cyanophenyl)-5-(4-methylphenyl)pyrimidin-2-yl]oxy}methyl)pyrrolidine-1 - Carboxylate was obtained as a yellow amorphous foam. The foam was dissolved in DCM (2 mL) and then TFA (2 mL) was added dropwise. The reaction was stirred at ambient temperature for 30 min and concentrated in vacuo to give the TFA salt of the title compound (35 mg, 30%) as an off-white amorphous foam. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.70 - 1.96 (m, 1 H), 2.05 - 2.23 (m, 1 H), 2.31 (s, 3 H), 2.76 - 2.91 (m, 1 H), 3.00 - 3.13(m, 1 H), 3.13 - 3.24(m, 1 H), 3.25 - 3.35(m, 1 H), 3.35 - 3.48(m, 1 H), 4.34 - 4.52(m, 2 H) H), 7.01 - 7.13(m, 2 H), 7.18(d, J =8.08 Hz, 2 H), 7.55(d, J =8.34 Hz, 2 H), 7.83(d, J =8.34 Hz, 2 H) ), 8.67 (s, 1 H), 8.69 - 8.87 (m, 2 H). [M+H] calcd for C ₂₃ H ₂₂ N ₄ O, 371; found value, 371.

Preparation 21A: tert -Butyl( 3aR , 6aS )-5-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-octahydropyrrolo[3,4-c] pyrrole-2-carboxylate

To a vial containing 4-(2,5-dichloropyrimidin-4-yl)benzonitrile (144 mg, 0.58 mmol) in ethanol (2 mL) was added with tert -butyl( 3aR , 6aS )-octahydropyrrole. [3,4-c]pyrrole-2-carboxylate (123 mg, 0.58 mmol), and DIEA (144 μl, 1.2 mmol) were added. The reaction was stirred at 100 °C for 1 hour. The reaction was concentrated in vacuo and the residue was purified by column chromatography (0-50% gradient EtOAc in hexanes) to give the title compound (242 mg, 98%) as a yellow amorphous solid. [M+H] calcd for C ₂₂ H ₂₄ N ₅ O ₂ Cl, 426; found value, 426.

Example 21: 4-{2-[(3a R ,6a S )-octahydropyrrolo[3,4-c]pyrrol-2-yl]-5-(4-methylphenyl)pyrimidin-4-yl} benzonitrile

Following the procedure for the preparation of Example 16, the TFA salt of the title compound was prepared by tert -butyl( 3aR , 6aS )-5-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl] It was prepared in 33% yield using -octahydropyrrolo[3,4-c]pyrrole-2-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 2.29 (s, 3 H), 2.98 - 3.27 (m, 4 H), 3.46 (m, 2 H), 3.60 - 3.70 (m, 2 H) , 3.72 - 3.83 (m, 2 H), 7.01 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 7.83 Hz, 2 H), 7.52 (d, J = 8.34 Hz, 2 H), 7.81 (d, J = 8.08 Hz, 2 H), 8.44 (s, 1 H), 8.78 - 8.98 (m, 2 H). [M+H] calcd for C ₂₄ H ₂₃ N ₅ , 382; found value, 382.

Example 22: 4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared starting from tert -butyl octahydro-1H-pyrrolo[3,4-c]pyridine-2-carboxylate in 37% yield. ¹ H NMR (400 MHz, methanol- d ₄ ): δ ppm 1.53 - 1.70 (m, 1 H), 1.84 - 1.99 (m, 1 H), 2.32 (s, 3 H), 2.59 - 2.75 (m, 2 H), 2.99 - 3.11(m, 1 H), 3.18 - 3.28(m, 1 H), 3.37 - 3.48(m, 3 H), 3.68 - 3.82(m, 1 H), 4.41 - 4.61(m, 2 H) H), 6.94 - 7.06 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 8.08 Hz, 2 H), 7.54 - 7.59 (d, J = 8.08 Hz, 2 H), 7.63 (d, J = 8.08 Hz, 3 H), 8.38 (s, 1 H). [M+H] calcd for C ₂₅ H ₂₅ N ₅ , 396; found value, 396.

Example 23: 4-{2-[(3a R ,8a S )-decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-methylphenyl)pyrimidin-4-yl }benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared from tert -butyl( 3aR , 8aS )-decahydropyrrolo[3,4-d]azepine-2-carboxylate at 28% Manufactured in yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.62 - 1.79 (m, 2 H), 1.82 - 1.99 (m, 2 H), 2.29 (s, 3 H), 2.55 - 2.65 (m, 2 H), 2.76 - 2.95 (m, 2 H), 3.28 - 3.40 (m, 2 H), 3.40 - 3.54 (m, 2 H), 4.25 - 4.43 (m, 2 H), 7.00 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 7.83 Hz, 2 H), 7.51 (d, J = 8.59 Hz, 2 H), 7.80 (d, J = 8.59 Hz, 2 H), 8.43 (s, 1 H), 8.53 - 8.64 (m, 1 H), 8.64 - 8.79 (m, 1 H). [M+H] calcd for C ₂₆ H ₂₇ N ₅ , 410; found value, 410.

Example 24: 4-{2-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-fluorophenyl)pyrimidin-4-yl }benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared by tert -butyl(3aR,8aS)-6-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-deca It was prepared using hydropyrrolo[3,4-d]azepine-2-carboxylate and (4-fluorophenyl)boronic acid in 32% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.62 - 1.79 (m, 2 H), 1.82 - 1.99 (m, 2 H), 2.50 - 2.62 (m, 2 H), 2.77 - 2.93 (m , 2 H), 3.30 - 3.42 (m, 2 H), 3.42 - 3.55 (m, 2 H), 4.26 - 4.42 (m, 2 H), 7.14 - 7.20 (m, 4 H), 7.50 (d, J = 8.34 Hz, 2 H), 7.81 (d, J = 8.34 Hz, 2 H), 8.40 - 8.52 (m, 1 H), 8.52 - 8.64 (m, 1 H), 8.67 - 8.79 (m, 1 H) . [M+H] calcd for C ₂₅ H ₂₄ N ₅ F, 414; found value, 414.

Example 25: 4-(2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl)benzonitrile

tert -butyl( 3R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino } It was prepared using methyl)pyrrolidine-1-carboxylate and (4-trifluoromethylphenyl)boronic acid in 46% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.65 - 1.81 (m, 1 H), 2.00 - 2.14 (m, 1 H), 2.59 - 2.73 (m, 1 H), 2.89 - 2.99 (m , 1 H), 3.09 - 3.20 (m, 1 H), 3.21 - 3.37 (m, 2 H), 3.38 - 3.50 (m, 2 H), 7.35 (d, J = 8.08 Hz, 2 H), 7.44 - 7.57 (m, 2 H), 7.67 (d, J = 8.08 Hz, 2 H), 7.80 (d, J = 8.34 Hz, 2 H), 8.46 (s, 1 H), 8.65 (br. s., 2 H). [M+H] calcd for C ₂₃ H ₂₀ N ₅ F ₃ , 424; found value, 424.

Example 26: 4-[5-(2-cyclopropylethynyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile

tert -butyl(3 R )-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)pyrrolidine-1-carboxyl in ACN (3 mL) Cyclopropane acetylene (33 mg, 0.5 mmol), PdCl ₂ (ACN) ₂ (2.6 mg, 0.01 mmol), XPhos (4 mg, 0.02), and K ₂ CO ₃ (103 mg, 0.75 mmol) was added. The mixture was purged with N ₂ for 2 min and sealed. The reaction was held at 100 °C for 16 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (0-50% gradient EtOAc in hexanes) to give a yellow amorphous residue. The residue was dissolved in DCM (2 mL) then TFA (2 mL) was added dropwise. The reaction was stirred at ambient temperature for 30 min and concentrated in vacuo. The residue was further purified by prep-HPLC (gradient 5%-95% ACN in water containing 0.1% HCO ₂ H) to give the formic acid salt of the title compound as a yellow amorphous foam (3 mg, 3%). ¹ H NMR (400 MHz, CD ₃ OD): δ ppm 0.58 - 0.75 (m, 2 H), 0.80 - 0.96 (m, 2 H), 1.36 - 1.53 (m, 1 H), 1.72 - 1.93 (m, 1 H), 2.10 - 2.31(m, 1 H), 2.66 - 2.82(m, 1 H), 2.95 - 3.09(m, 1 H), 3.51 - 3.62(m, 5 H), 7.76 - 7.90(m, 2 H), 8.14 - 8.27 (m, 2 H), 8.34 - 8.45 (m, 1 H). [M+H] calcd for C ₂₁ H ₂₁ N ₅ , 344; found value, 344.

Example 27: 4-(2-{[(3aR,5S,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]amino}-5-(4-methylphenyl)pyrimidin-4-yl)benzo nitrile

tert -Butyl(3aR,5S,6aS)-5-{[5-chloro-4-(4-cyanophenyl)pyrimidine-2- prepared according to the procedure for Preparation 16B in dioxane (3 mL) In a vial containing yl]amino}-octahydrocyclopenta[c]pyrrole-2-carboxylate (250.0 mg, 0.57 mmol) (4-methylphenyl)boronic acid (155.0 mg, 1.14 mmol), Pd(dppf)Cl ₂ (80.0 mg, 0.11 mmol), and Na ₂ CO ₃ (1 mL, 2 M) were added. The mixture was purged with N ₂ for 2 min and sealed. The reaction mixture was irradiated in a microwave at 130° C. for 4 hours. Water was added and the mixture was extracted with EtOAc (3X). The combined organic layers were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1) to give a crude residue. HCl (5 mL, 4 M in dioxane) was added to the mixture and stirred at 30 °C for 1 hour. The mixture was concentrated in vacuo and purified by prep-HPLC to give the title compound (40.0 mg, yield 33.7%) as a pale yellow foam. ¹ H NMR (methanol- d ₄ , 400 MHz): δ 1.87 - 1.84 (m, 4 H), 2.32 (s, 3 H), 2.63 - 2.59 (m, 2 H), 2.80 - 2.70 (m, 2 H) ), 3.12 - 3.07 (m, 2 H), 4.47 - 4.40 (m, 1 H), 6.98 (d, J = 8.0 Hz, 2 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.54 ( d, J = 8.4 Hz, 2 H), 7.62 (d, J = 8.4 Hz, 2 H), 8.29 (s, 1 H). [M+H] calcd for C ₂₅ H ₂₅ N ₅ , 396; found value, 396.

Example 28: (±) -4- (2-{[(3-fluoropyrrolidin-3-yl)methyl]amino}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

The title compound was prepared according to the procedure for the preparation of Example 27 (±) -tert - butyl-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl) It was prepared in 29% yield using -3-fluoropyrrolidine-1-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (methanol- d ₄ , 400 MHz): δ 2.00 - 2.15 (m, 2 H), 2.34 (s, 3 H), 3.17 - 2.96 (m, 4 H), 3.95 (d, J = 19.2 Hz , 2 H), 7.02 (d, J = 8.8 Hz, 2 H), 7.14 (d, J = 8.8 Hz, 2 H), 7.57 (d, J = 8.8 Hz, 2 H), 7.65 (d, J = 8.8 Hz, 2 H ) 8.8 Hz, 2 H), 8.35 (s, 1 H). [M+H] calcd for C ₂₃ H ₂₂ N ₅ F, 388; found, 388.

Example 29: (±) - 4-[5-(4-methylphenyl)-2-[(piperidin-3-yl)amino]pyrimidin-4-yl]benzonitrile

Following the procedure for the preparation of Example 27, the title compound was prepared from tert -butyl 3-{[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}piperidine-1-carboxylate and (4-methylphenyl) boronic acid in a yield of 29%. ¹ H NMR (CDCl ₃ , 400 MHz): δ 8.34 (s, 1 H), 7.56 - 7.50 (m, 4 H), 7.11 (d, J = 8.0 Hz, 2 H), 6.97 (d, J = 8.0 Hz, 2 H), 5.53 - 5.51 (m, 1 H), 4.11 - 4.07 (m, 1 H), 3.31 - 3.27 (m, 1 H), 2.95 - 2.85 (m, 1 H), 2.79 - 2.67 ( m, 2 H), 2.36 (s, 3 H), 2.05 - 1.95 (m, 1 H), 1.83 - 1.79 (m, 2 H), 1.70 - 1.60 (m, 2 H). [M+H] calcd for C ₂₃ H ₂₃ N ₅ , 370; found value, 370.

Example 30: 4-[5-(4-methylphenyl)-2-[(piperidin-4-yl)amino]pyrimidin-4-yl]benzonitrile

Following the procedure for the preparation of Example 27, the title compound was prepared by tert -butyl-4-{[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}piperidine-1-carboxyl It was prepared in 17% yield using rate and (4-methylphenyl)boronic acid. ¹ H NMR (methanol- d ₄ , 400 MHz): δ 8.31 (s, 1 H), 7.64 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.13 ( d, J = 8.0 Hz, 2 H), 7.05 (d, J = 8.0 Hz, 2 H), 4.03 - 4.01 (m, 1 H), 3.14 - 3.10 (m, 2 H), 2.77 - 2.71 (m, 2 H), 2.34 (s, 3 H), 2.10 - 2.07 (m, 2 H), 1.58 - 1.52 (m, 2 H). [M+H] calcd for C ₂₃ H ₂₃ N ₅ , 370; found value, 370.

Example 31: (±) - 4-[5-(4-methylphenyl)-2-[(piperidin-3-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

The title compound was prepared according to the procedure for the preparation of Example 27 (±) -tert - butyl-3-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl) It was prepared in 18% yield using piperidine-1-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (methanol- d ₄ , 400 MHz): δ 8.29 (s, 1 H), 7.63 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.12 ( d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 3.35 - 3.31 (m, 2 H), 3.14 - 3.11 (m, 1 H), 3.00 - 2.97 (m, 1 H), 2.57 - 2.56(m, 1 H), 2.40 - 2.32(m, 4 H), 1.93 - 1.91(m, 2 H), 1.75 - 1.72(m, 1 H), 1.54 - 1.47(m, 2H). [M+H] calcd for C ₂₄ H ₂₅ N ₅ , 384; found value, 384.

Example 32: 4-[5-(4-methylphenyl)-2-[(piperidin-4-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

Following the procedure for the preparation of Example 27, the title compound was prepared by tert -butyl-4-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}methyl)piperidine- It was prepared in 35% yield using 1-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (methanol- d ₄ , 400 MHz): δ 8.29 (s, 1 H), 7.64 (d, J = 8.0 Hz, 2 H), 7.56 (d, J = 8.0 Hz, 2 H), 7.13 ( d, J = 8.0 Hz, 2 H), 7.00 (d, J = 8.0 Hz, 2 H), 3.39 - 3.36 (m, 2 H), 3.09 - 3.05 (m, 2 H), 2.63 - 2.59 (m, 2 H), 2.34 (s, 3 H), 1.83 - 1.79 (m, 3 H), 1.31 - 1.23 (m, 2 H). [M+H] calcd for C ₂₄ H ₂₅ N ₅ , 384; found value, 384.

Example 33: (±) -4- [5-(4-methylphenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

(±) -tert -butyl 2-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}-tert-butyl 2-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino} It was prepared in 19% yield using methyl)morpholine-4-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 2.28 (s, 3 H), 2.75 - 2.91 (m, 1 H), 2.92 - 3.09 (m, 1 H), 3.10-3.17 (m, 1 H), 3.24 - 3.34(m, 1 H), 3.36 - 3.59(m, 2 H), 3.62 - 3.77(m, 1 H), 3.86 - 3.94(m, 1 H), 3.94 - 4.02(m, 1 H) H), 7.00 (d, J = 8.08 Hz, 2 H), 7.12 (d, J = 7.83 Hz, 2 H), 7.42 - 7.53 (m, 2 H), 7.55 - 7.65 (m, 1 H), 7.80 (d, J = 8.08 Hz, 2 H), 8.37 (s, 1 H), 8.64 - 8.94 (m, 2 H). [M+H] calcd for C ₂₂ H ₂₂ N ₅ O, 386; found, 386.

Example 34: (±) - 4-[5-(4-fluorophenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile

(±) -tert -butyl 2-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino}-tert-butyl 2-({[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]amino} It was prepared using methyl)morpholine-4-carboxylate and (4-fluorophenyl)boronic acid in 44% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 2.74 - 2.93 (m, 1 H), 2.93 - 3.10 (m, 1 H), 3.17 - 3.22 (m, 1 H), 3.24 - 3.34 (m , 1 H), 3.36 - 3.59 (m, 2 H), 3.61 - 3.77 (m, 1 H), 3.84 - 3.95 (m, 1 H), 3.96-4.00 (m, 1 H), 7.16 (d, J = 7.07 Hz, 4 H), 7.40 - 7.59 (m, 2 H), 7.60 - 7.74 (m, 1 H), 7.81 (d, J = 8.34 Hz, 2 H), 8.40 (s, 1 H), 8.65 - 8.98 (m, 2 H). Calcd [M+H] for C ₂₂ H ₂₀ N ₅ OF, 390; found value, 390.

Example 35: 4-(2-{2,7-diazaspiro[4.4]nonan-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared starting from tert -butyl 2,7-diazaspiro[4.4]nonane-2-carboxylate in 24% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.88 - 2.17 (m, 4 H), 2.28 (s, 3 H), 3.08 - 3.41 (m, 4 H), 3.55 - 3.63 (m, 1 H), 3.63 - 3.73 (m, 3 H), 7.00 (d, J = 8.08 Hz, 2 H), 7.12 (d, J = 7.83 Hz, 2 H), 7.51 (d, J = 8.08 Hz, 2 H) ), 7.80 (d, J = 8.34 Hz, 2 H), 8.45 (s, 1 H), 8.74 - 9.01 (br. s., 2 H). [M+H] calcd for C ₂₅ H ₂₅ N ₅ , 396; found value, 396.

Example 36: 4-(2-{2,8-diazaspiro[4.5]decan-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

The TFA salt of the title compound was converted to tert- butyl 2-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-2,8-diazaspiro according to the procedure for the preparation of Example 21. It was prepared in 42% yield using [4.5]decane-8-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.65 - 1.82 (m, 4 H), 1.90 - 1.99 (m, 2 H), 2.28 (m, 3 H), 3.13 (br. s., 4 H), 3.52(s, 2 H), 3.66(t, J = 6.95 Hz, 2 H), 7.00(s, 2 H), 7.12(d, J = 7.83 Hz, 2 H), 7.52(d, J = 8.34 Hz, 2 H), 7.80 (d, J = 8.59 Hz, 2 H), 8.29 - 8.54 (m, 3 H). [M+H] calcd for C ₂₆ H ₂₇ N ₅ , 410; found value, 410.

Example 37: 4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-2-yl}pyrimidin-4-yl]benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared by tert -butyl-2-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-octahydro-1H-p It was prepared in 42% yield using rollo[3,4-c]pyridine-5-carboxylate and (4-methylphenyl)boronic acid. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.60 - 1.79 (m, 1 H), 1.84 - 2.01 (m, 1 H), 2.28 (s, 3 H), 2.50-2.62 (m, 2 H), 2.96 - 3.20 (m, 3 H), 3.20 - 3.35 (m, 1 H), 3.53 - 3.76 (m, 4 H), 7.01 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 7.83 Hz, 2 H), 7.52 (d, J = 8.34 Hz, 2 H), 7.80 (d, J = 8.34 Hz, 2 H), 8.42 (s, 1 H), 8.47 - 8.69 (m, 1 H). [M+H] calcd for C ₂₅ H ₂₅ N ₅ , 396; found value, 396.

Example 38: 4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared starting from tert -butyl octahydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate in 48% yield. ¹ H NMR (400 MHz, methanol- d ₄ ): δ ppm 1.77 - 2.00 (m, 2 H), 2.05 - 2.23 (m, 2 H), 2.32 (s, 3 H), 2.56 - 2.69 (m, 1 H), 3.42 - 3.55(m, 3 H), 3.79 - 3.88(m, 1 H), 3.90 - 4.02(m, 1 H), 4.30 - 4.40(m, 1 H), 4.40 - 4.52(m, 1 H) H), 6.99 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 7.83 Hz, 2 H), 7.52 - 7.59 (d, J = 8.14 Hz, 2 H), 7.63 (d, J = 8.14 Hz, 2 H ) 8.34 Hz, 2 H), 8.34 - 8.44 (m, 1 H). [M+H] calcd for C ₂₅ H ₂₅ N ₅ , 396; found value, 396.

Example 39: 4-(2-{2,8-diazaspiro[4.5]decan-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

Following the procedure for the preparation of Example 21, the TFA salt of the title compound was prepared starting from tert- butyl 2,8-diazaspiro[4.5]decane-2-carboxylate in 62% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.50 - 1.71 (m, 4 H), 1.84 - 1.94 (m, 2 H), 2.28 (s, 3 H), 3.02 - 3.11 (m, 2 H), 3.23 - 3.38 (m, 2 H), 3.73 - 3.95 (m, 4 H), 7.01 (d, J = 8.08 Hz, 2 H), 7.13 (d, J = 8.08 Hz, 2 H), 7.51 (d, J = 8.34 Hz, 2 H), 7.80 (d, J = 8.34 Hz, 2 H), 8.43 (s, 1 H), 8.84 (br. s., 2 H). [M+H] calcd for C ₂₆ H ₂₇ N ₅ , 410; found value, 410.

Example 40: 4-(2-{1,8-diazaspiro[4.5]decan-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile

The TFA salt of the title compound was prepared from tert -butyl 1,8-diazaspiro[4.5]decane-1-carboxylate in 64% yield following the procedure for the preparation of Example 21. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 1.77 - 1.92 (m, 4 H), 1.93 - 2.08 (m, 4 H), 2.29 (s, 3 H), 3.20 - 3.35 (m, 2 H), 3.45 - 3.58 (m, 2 H), 4.27 - 4.41 (m, 2 H), 7.02 (d, J = 7.83 Hz, 2 H), 7.13 (d, J = 7.83 Hz, 2 H), 7.52 (d, J = 8.34 Hz, 2 H), 7.81 (d, J = 8.34 Hz, 2 H), 8.46 (s, 1 H) 8.64 - 8.79 (m, 1 H). [M+H] calcd for C ₂₆ H ₂₇ N ₅ , 410; found value, 410.

Example 41: 4-[5-(4-methylphenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}pyrimidin-4-yl]benzonitrile

tert -butyl-7-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-9-oxa-3, Prepared using 7-diazabicyclo[3.3.1]nonane-3-carboxylate and (4-methylphenyl)boronic acid in 26% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 2.30 (s, 3 H), 3.27 - 3.44 (m, 4 H), 3.44 - 3.55 (m, 1 H), 3.62 - 3.75 (m, 1 H), 4.27 (m, 2 H), 4.25 - 4.33 (m, 4 H), 4.57 (d, J = 13.39 Hz, 2 H), 7.04 (d, J = 8.08 Hz, 2 H), 7.17 (d , J = 7.83 Hz, 2 H), 7.56 (d, J = 8.59 Hz, 2 H), 7.83 (d, J = 8.59 Hz, 2 H), 8.13 - 8.38 (m, 1 H), 8.52 - 8.64 ( m, 1 H), 9.43 (br. s., 1 H). [M+H] calcd for C ₂₄ H ₂₃ N ₅ O, 398; found value, 398.

Example 42: 4-[5-(4-fluorophenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}pyrimidin-4-yl]benzo nitrile

tert -butyl-7-[5-chloro-4-(4-cyanophenyl)pyrimidin-2-yl]-9-oxa-3, Prepared using 7-diazabicyclo[3.3.1]nonane-3-carboxylate and (4-fluorophenyl)boronic acid in 20% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ): δ ppm 3.25 - 3.44 (m, 4 H), 3.44 - 3.53 (m, 2 H), 3.66-3.69 (m, 2 H), 4.28 (br. s ., 2 H), 4.57 (d, J = 13.39 Hz, 2 H), 7.17 - 7.25 (m, 4 H), 7.54 ( d , J = 8.59 Hz, 2 H), 7.85 (d, J = 8.59 Hz) , 2 H), 8.13 - 8.31 (m, 1 H), 8.60 (s, 1 H), 9.20 - 9.41 (m, 1 H). Calcd [M+H] for C ₂₃ H ₂₀ N ₅ OF, 402; Actual value, 402.

Preparation 43A: Methyl 1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylate

A mixture of methyl 4-(4-methylphenyl)-2,4-dioxobutanoate (1.0 g, 4.55 mmol) and 4-hydrazinylbenzonitrile (0.85 g, 5.0 mmol) in AcOH (20 mL) was 118 It was stirred for 16 hours at °C. The solvent was removed in vacuo and the residue was purified by column chromatography (0-80%, EtOAc:PE) to yield 1.3 g (90%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.65 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.18 (d, J = 8.0 Hz, 2 H) , 7.10 (d, J = 8.0 Hz, 2 H), 7.02 (s, 1 H), 3.99 (s, 3 H), 2.39 (s, 3 H). [M+H] calcd for C ₁₉ H ₁₅ N ₃ O ₂ , 318; found value, 318.

Preparation 43B: 1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylic acid

Methyl 1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylate (1.3 g, 4.1 mmol) and LiOH (0.3 g) in MeOH/H ₂ O (20 mL/20 mL) , 12.3 mmol) was stirred at room temperature for 3 hours. MeOH was removed in vacuo and H ₂ O (20 mL) was added. The pH of the solution was adjusted to 4 using HCl (0.6 M) solution. The mixture was extracted with DCM (80 mL x 3), washed with brine (50 mL x 2) and dried over Na ₂ SO ₄ . The solvent was evaporated in vacuo to yield 1.1 g (88%) of the title compound as a yellow solid. ¹ H NMR (methanol-d4, 400 MHz): δ 7.78 (d, J = 8.4 Hz, 2 H), 7.52 (d, J = 8.8 Hz, 2 H), 7.21 (d, J = 8.0 Hz, 2 H) ), 7.15 (d, J = 8.0 Hz, 2 H), 7.02 (s, 1 H), 2.35 (s, 3 H). [M+H] calcd for C ₁₈ H ₁₃ N ₃ O ₂ , 304; found value, 304.

Preparation 43C: tert -Butyl N-[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate

1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazole-3-carboxylic acid (1.1 g, 3.63 mmol), DPPA (1.2 g, 4.36 mmol) and TEA (0.44 g, 4.36 mmol) were stirred at 110 °C for 16 h. The solvent was removed in vacuo and the crude residue was purified by column chromatography (0-50%, EtOAc:PE) to yield 0.3 g (22%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.58-7.56 (d, J = 8.0 Hz, 2 H), 7.36-7.34 (d, J = 8.0 Hz, 2 H), 7.18-7.13 (m, 5 H ), 6.81 (br. S., 1 H), 2.38 (s, 3 H), 1.54 (s, 9 H). [M+H] calcd for C ₂₂ H ₂₂ N ₄ O ₂ , 375; found value, 375.

Preparation 43D: tert -Butyl 3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2-yl)oxycarbo Nyl]amino]methyl]pyrrolidine-1-carboxylate

tert -butyl N- [1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate (80 mg, 0.21 mmol), tert -butyl 3 in DMF (6 mL) A mixture of -[(4-methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate (92 mg, 0.25 mmol) and Cs ₂ CO ₃ (210 mg, 0.64 mmol) was refluxed at 90 °C for 16 h. . The mixture was extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL x 2) and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the crude residue was purified by prep-HPLC to yield 76 mg (63%) of the title compound as a yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.57 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.19-7.12 (m, 4 H), 6.80 ( brs, 1 H), 4.05-3.95 (m, 2 H), 3.51 (m, 2 H), 3.38-3.26 (m, 1 H), 3.17 (dd, J ₁ = 8.0 Hz, J ₂ = 12.0 Hz, 1 H), 2.75 (m, 1 H), 2.39 (s, 3 H), 2.03-1.93 (m, 1 H), 1.78-1.68 (m, 1 H), 1.57 (s, 9 H) ), 1.45 (s, 9 H). [M+H] calcd for C ₃₂ H ₃₉ N ₅ O ₄ , 558; found, 558.

Example 43: 4-[5-(4-methylphenyl)-3-(pyrrolidin-3-ylmethylamino)pyrazol-1-yl]benzonitrile

tert -Butyl 3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2-yl) in DCM (2 mL) To a solution of oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate (76 mg, 0.09 mmol) was added HCl/dioxane (4 M, 5 mL) dropwise at 0°C to -10°C. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The crude residue was purified by prep-HPLC to yield 24 mg (39%) of the title compound as a yellow oil. ¹ H NMR (methanol-d4, 400 MHz): δ 8.53 (brs, 1 H), 7.63 (d, J = 8.0 Hz, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.20 (d , J = 8.0 Hz, 2 H), 7.13 (d, J = 8.0 Hz, 2 H), 5.94 (s, 1 H), 3.46-3.38 (m, 2 H), 3.38-3.32 (m, 2 H) , 3.30-3.25 (m, 1 H), 3.12 (dd, J ₁ = 8.0 Hz, J ₂ = 12.0 Hz, 1 H), 2.78 (m, 1 H), 2.36 (s, 3 H), 2.27-2.17 (m, 1 H), 1.86 (m, 1 H). [M+H] calcd for C ₂₂ H ₂₃ N ₅ , 358; found, 358.

Preparation 44A: tert -Butyl( 3S )-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2- yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate

The title compound was prepared by tert -butyl N- [1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate and tert -butyl ( 3S ) according to the procedure for Preparation 43D. Prepared at 34% from -3-[(4-methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate. ¹ H NMR (CDCl ₃ , 400 MHz) δ 7.57 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.21 - 7.09 (m, 4 H), 6.82 (br s., 1 H), 4.07 - 3.91 (m, 2 H), 3.58 - 3.41 (m, 2 H), 3.32 (m, 1 H), 3.16 (br. s., 1 H), 2.75 (m , 1 H), 2.38 (s, 3 H), 1.98 (m, 1 H), 1.73 (m, 1 H), 1.60 - 1.53 (s, 9 H), 1.45 (s, 9 H). [M+H] calcd for C ₃₂ H ₃₉ N ₅ O ₄ , 558; found, 558.

Example 44 4-[5-(4-methylphenyl)-3-[[ (3S )-pyrrolidin-3-yl]methylamino]pyrazol-1-yl]benzonitrile

Following the procedure for the preparation of Example 43, the title compound was prepared by tert -butyl( 3S )-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]- Prepared from [(2-methylpropan-2-yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate in 59% yield. ¹ H NMR (methanol-d4, 400 MHz): δ 7.80 - 7.74 (m, 2 H), 7.51 - 7.45 (m, 2 H), 7.26 - 7.17 (m, 4 H), 3.52 (dd, J ₁ = 8.0 Hz, J ₂ = 12.0 Hz, 1 H), 3.48 - 3.40 (m, 3 H), 3.35-3.27 (m, 1 H), 3.12 (dd, J ₁ = 8.0 Hz, J ₂ = 12.0 Hz, 1 H), 2.84 - 2.76 (m, 1 H), 2.36 (s, 3 H), 2.33 - 2.23 (m, 1 H), 1.87 - 1.84 (m, 1 H). [M+H] calcd for C ₂₂ H ₂₃ N ₅ , 358; found, 358.

Preparation 45A: tert -Butyl( 3R )-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2- yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate

tert -butyl N- [1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate and tert -butyl( 3R ) Prepared at 40% from -3-[(4-methylphenyl)sulfonyloxymethyl]pyrrolidine-1-carboxylate. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.57 (d, J = 8.0 Hz, 2 H), 7.37 (J = 8.0 Hz, 2 H), 7.21 - 7.09 (m, 4 H), 6.82 (br. s, 1 H), 4.08 - 3.90 (m, 2 H), 3.58 - 3.41 (m, 2 H), 3.34 - 3.30 (m, 1 H), 3.17 (br. s, 1 H), 2.75 (m, 1 H), 2.39(s, 3 H), 2.04 - 1.93(m, 1 H), 1.73(m, 1 H), 1.53 - 1.61(s, 9 H), 1.45(s, 9 H). [M+H] calcd for C ₃₂ H ₃₉ N ₅ O ₄ , 558; found, 558.

Example 45 4-[5-(4-methylphenyl)-3-[[ (3R )-pyrrolidin-3-yl]methylamino]pyrazol-1-yl]benzonitrile

Following the procedure for the preparation of Example 43, the title compound was prepared by tert -butyl( 3R )-3-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]- Prepared from [(2-methylpropan-2-yl)oxycarbonyl]amino]methyl]pyrrolidine-1-carboxylate in 33% yield. ¹ H NMR (methanol-d4, 400 MHz): δ 7.79 - 7.70 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.4 Hz, 2 H), 7.26 - 7.15 (m, 4 H) , 3.51 (m, 1 H), 3.47 - 3.39 (m, 3 H), 3.34 - 3.30 (m, 1 H), 3.12 (m, 1 H), 2.86 - 2.75 (m, 1 H), 2.36 (s , 3 H), 2.32 - 2.22 (m, 1 H), 1.87 (m, 1 H). [M+H] calcd for C ₂₂ H ₂₃ N ₅ , 358; found, 358.

Preparation 46A: tert-Butyl 4-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan-2-yl)oxycarbo Nyl]amino]methyl]piperidine-1-carboxylate

tert -butyl N- [1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate (80 mg, 0.21 mmol), tert-butyl 4 in DMF (6 mL) A mixture of -[(4-methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate ( 72 mg, 0.26 mmol) and Cs ₂ CO ₃ (210 mg, 0.64 mmol) was refluxed at 90 °C for 16 h. . The mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the crude residue was purified by column chromatography (0-33%, EtOAc:PE) to yield 82 mg (67%) of the title compound as a yellow solid. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.57 (d, J = 8.4 Hz, 2 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.20 - 7.12 (m, 4 H), 6.80 ( br. S., 1 H), 4.17 - 4.04 (m, 2 H), 3.87 (d, J = 7.2 Hz, 2 H), 2.70 (t, J = 12.4 Hz, 2 H), 2.41 (s, 3 H), 2.09 - 1.98(m, 1 H), 1.70(d, J = 12.4 Hz, 2 H), 1.56(s, 9 H), 1.47(s, 9 H), 1.32-1.19(m, 2 H) ). [M+H] calcd for C ₃₃ H ₄₁ N ₅ O ₄ , 572; found value, 572.

Example 46: 4-[5-(4-methylphenyl)-3-(piperidin-4-ylmethylamino)pyrazol-1-yl]benzonitrile

tert -butyl 4-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[ Prepared from (2-methylpropan-2-yl)oxycarbonyl]amino]methyl]piperidine-1-carboxylate in 57% yield. ¹ H NMR (methanol-d4, 400 MHz): δ 8.51 (brs, 2 H), 7.65 (d, J = 8.0 Hz, 2 H), 7.36 (d, J = 8.0 Hz, 2 H), 7.22 (d , J = 8.0 Hz, 2 H), 7.15 (d, J = 8.0 Hz, 2 H), 5.95 (s, 1 H), 3.44 (d, J = 12.0 Hz, 2 H), 3.22 (d, J = 12.0 Hz, 2 H) 6.4 Hz, 2 H), 3.05-2.98 (m, 2 H), 2.38 (s, 3 H), 2.16-1.98 (m, 3 H), 1.56-1.41 (m, 2 H). [M+H] calcd for C ₂₃ H ₂₅ N ₅ , 372; found value, 372.

Preparation 47A: tert -Butyl( 1S,5R )-6-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methylpropan- 2-yl)oxycarbonyl]amino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate

tert -butyl N- [1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]carbamate (50.0 mg, 0.133 mmol) in DMF (6 mL), tert-butyl ( A mixture of 1S,5R )-6-(chloromethyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (41.0 mg, 0.14 mmol) and Cs ₂ CO ₃ (130.0 mg, 0.4 mmol) was added to 90 refluxed for 16 hours at °C. The mixture was extracted with EA (20 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and dried over Na ₂ SO ₄ . The solvent was evaporated in vacuo to give the crude product which was purified by prep-HPLC to give the title compound (38.0 mg, 50.0%) as a yellow oil. ¹ H NMR (CDCl ₃ , 400 MHz): δ 7.58 (d, J = 8.0 Hz, 2 H), 7.37 (d, J = 8.0 Hz, 2 H), 7.19 - 7.13 (m, 4 H), 6.80 ( br. s, 1 H), 3.88 (d, J = 6.8 Hz, 2 H), 3.62 - 3.47 (m, 2 H), 3.39 - 3.28 (m, 2 H), 2.39 (s, 3 H), 1.62 (s, 2 H), 1.57 (s, 9 H), 1.44 - 1.40 (s, 9 H), 1.17 (m, 1 H). [M+H] calcd for C ₃₃ H ₃₉ N ₅ O ₄ , 570; found value, 570.

Example 47: 4-[3-[[( 1S,5R )-3-azabicyclo[3.1.0]hexan-6-yl]methylamino]-5-(4-methylphenyl)pyrazol-1-yl] benzonitrile

tert -butyl( 1S,5R )-6-[[[1-(4-cyanophenyl)-5-(4-methylphenyl)pyrazol-3-yl]-[(2-methyl in DCM (5 mL) To a solution of propan-2-yl)oxycarbonyl]amino]methyl]-3-azabicyclo[3.1.0]hexane-3-carboxylate (38.0 mg, 0.067 mmol) in HCl/dioxane (4 M, 10 mL ) was added dropwise at 0 ° C to -10 ° C. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the crude product, which was purified by prep-HPLC to give the title compound (24.0 mg, 38.7%) as a yellow oil. ¹ H NMR (methanol-d ₄ , 400 MHz): δ 7.72 (d, J = 8.0 Hz, 2 H), 7.43 (d, J = 7.6 Hz, 2 H), 7.24 - 7.14 (m, 4 H), 3.47 - 3.39 (m, 4 H), 3.34 - 3.31 (m, 2 H), 2.35 (s, 3 H), 1.91 (br. s., 2 H), 1.36 (m, 1 H). [M+H] calcd for C ₂₃ H ₂₃ N ₅ , 370; found value, 370.

Production Example 48 : tert-Butyl 4-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl]piperidine-1-carboxylate

4-[5-(4-methylphenyl)-1H-pyrazolo[4,3-b]pyridin-6-yl]benzonitrile (80 mg, 0.258 mmol) and tert-butyl 4-bromide in DMF (10 mL) To a mixture of furperidin-1-carboxylate (341 mg, 1.29 mmol) was added Cs ₂ CO ₃ (252 mg, 0.77 mmol). The mixture was stirred overnight at 60 °C. The mixture was diluted with EtOAc (30 mL) and water (30 mL). The aqueous layer was extracted with EtOAc (50 mL x 3). The combined organic layers were washed with water (30 mL x 2), brine, dried over Na ₂ SO ₄ , filtered, concentrated, and purified by prep-HPLC to yield 48 mg (38%) of the title compound as a white solid. did ¹ H NMR (CDCl ₃ , 400 MHz) δ 8.32 (s, 1 H), 7.78 (s, 1 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 7.19 (d, J = 8.0 Hz, 2 H), 7.07 (d, J = 8.0 Hz, 2 H), 4.64 - 4.58 (m, 1 H), 4.36-4.32 (m, 2 H), 3.00 -2.95 (m, 2 H), 2.34 (s, 3 H), 2.30-2.23 (m, 2 H) 2.07 (d, J = 10.8 Hz, 2 H), 1.50 (s, 9 H). [M+H] calcd for C ₃₀ H ₃₁ N ₅ O ₂ , 494; found value, 494.

Example 48 : 4-[5-(4-methylphenyl)-1-piperidin-4-ylpyrazolo[4,3-b]pyridin-6-yl]benzonitrile

Following the procedure for the preparation of Example 3, the title compound was prepared from tert-butyl 4-[6-(4-cyanophenyl)-5-(4-methylphenyl)pyrazolo[4,3-b]pyridin-1-yl ]was prepared as HCl salt from piperidine-1-carboxylate in 75% yield. ¹ H NMR (DMSO-d6, 400 MHz) δ 9.67-9.64 (brs, 1 H), 9.50-9.48 (brs, 1 H), 8.45 (s, 1 H), 8.43 (s, 1 H), 7.81 ( d, J = 8.4 Hz, 2 H), 7.25 (d, J = 8.4 Hz, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 7.09 (d, J = 8.0 Hz, 2 H), 5.18-5.13(m, 1 H), 3.45-3.41(m, 2 H), 3.12-3.08(m, 2 H), 2.50 - 2.45(m, 2 H), 2.27(s, 3 H), 2.15- 2.13 (m, 2 H). [M+H] calcd for C ₂₅ H ₂₃ N, 394; found value, 394.

Preparation 49A . tert-Butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]carbamate

2,6-dichloropyrazine (5.0 g, 33.6 mmol), 4-(N-Boc-amino)piperidine (6.7 g, 33.6 mmol), and Et ₃ N (4.7 mL, 33.6 mmol) in NMP (50 mL) ) was heated to 120° C. for 2 hours. The resulting mixture was poured into ice water and extracted with ethyl acetate (3*100 mL). The organic layer was washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with PE/MTBE (5:1) to obtain crude tert -butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]carbamate (7.9 g, 75 %) was obtained as an off-white solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.38-1.45 (2H, m), 1.45 (9H, s) 2.04-2.09 (2H, m), 3.01-3.10 (2H, m), 3.69-3.74 (1H) , m), 4.20-4.27 (2H, m), 4.46-4.49 (1H, m), 7.78 (1H, s), 7.98 (1H, s). [M+H] calculated for C ₁₄ H ₂₁ ClN ₄ O ₂ , 313; found value, 313.

Preparation 49B . tert-Butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate

tert -butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]carbamate (1.0 g, 3.21 mmol) in ACN/H ₂ O (3:1, 24 mL) To a round bottom flask charged with (4-cyano-3-fluorophenyl)boronic acid (0.64 g, 3.85 mmol), Pd(OAc) ₂ (36 mg, 0.16 mmol), PPh ₃ (85 mg, 0.32 mmol) , and K ₃ PO ₄ (1.0 g, 4.82 mmol) were added. The reaction mixture was kept at reflux for 16 hours under a nitrogen atmosphere. After completion, the mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was triturated with PE to give tert -butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate (1.2 g, 94%) was obtained as an off-white solid. Calcd [M+H] for C ₂₁ H ₂₄ FN ₅ O ₂ , 398; found value, 398.

Preparation 49C . tert-Butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate

tert -butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}carbamate (1.2 g, 3.1 mmol) was added dropwise to NBS (0.61 g, 3.4 mmol) in ACN (5 mL). The mixture was stirred for 2 hours at ambient temperature. After completion, the reaction mixture was quenched with water and extracted with ethyl acetate (3*50 mL). The organic layer was washed successively with water, brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with PE/MTBE (5:1) to yield crude tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate (0.63 g, 43%) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.37-1.45 (2H, m), 1.45 (9H, s) 2.07-2.10 (2H, m), 3.04-3.11 (2H, m), 3.70-3.75 (1H) , m), 4.23–4.26 (2H, m), 4.47–4.49 (1H, m), 7.63 (1H, d, J = 9.6 Hz), 7.68–7.72 (2H, m), 7.93 (1H, s). Calcd [M+H] for C ₂₁ H ₂₃ BrFN ₅ O ₂ , 476; found value, 476.

Example 49 . 4-[6-(4-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile

tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperi in ACN/H 2 O ( ₃ :1, 48 mL) To a round bottom flask charged with din-4-yl}carbamate (0.6 g, 1.26 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (0.45 g, 2.56 mmol), Pd(OAc) ₂ (14 mg, 0.063 mmol), S-PHOS (54 mg, 0.13 mmol) and K ₃ PO ₄ (0.67 g, 3.15 mmol) were added. The mixture was heated to reflux for 16 hours under a nitrogen atmosphere. After completion, the reaction mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by column chromatography (50-100% ethyl acetate in PE gradient) and prep-HPLC to give a yellow solid. After the solid was suspended in ethyl acetate, HCl (6 mL, 10 M in ethyl acetate) was added and stirred for 2 hours at ambient temperature. After completion, the reaction mixture was concentrated in vacuo to give the title compound (0.22 g, 37%) as a yellow solid. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.73-1.81 (2H, m), 2.20-2.22 (2H, m), 3.22-3.28 (2H, m), 3.51-3.57 (1H, m), 4.37 (3H, s), 4.70-4.73 (2H, m), 7.37 (1H, d, J = 7.6 Hz), 7.51 (1H, d, J = 9.6 Hz), 7.56 (1H, d, J = 8.8 Hz) , 7.66 (1H, dd, J = 7.2 Hz, 7.6 Hz), 7.71 (1H, d, J = 8.8 Hz), 8.01 (1H, s), 8.52 (1H, s), 8.73 (1H, s). Calculated [M+H] for C ₂₄ H ₂₂ FN ₇ , 428; found value, 428.

Preparation Example 50A . tert-Butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]N-methylcarbamate

2,6-dichloropyrazine (1.0 g, 6.7 mmol), 4-(N-Boc-methylamino)piperidine ( 1.43 g, 6.7), and DIEA (1.7 g, 13 mmol) in DMF (20 mL) The filled round bottom flask was held at 100° C. for 2 hours. The resulting mixture was poured into ice water and extracted with ethyl acetate (3*100 mL). The organic layer was successively washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with PE to afford crude tert -butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4-yl]N-methylcarbamate (2.1 g, 96%) as an off-white color. Obtained as a solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.48 (9H, s) 1.65-1.80 (4H, m), 2.72 (3H, s), 2.92-3.00 (2H, m), 4.12-4.37 (1H, m) ), 4.40-4.46 (2H, m), 7.78 (1H, s), 7.99 (1H, s). [M+H] calculated for C ₁₅ H ₂₃ ClN ₄ O ₂ , 327; found value, 327.

Preparation Example 50B . tert-Butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}-N-methylcarbamate

tert -butyl-N-[1-(6-chloropyrazin-2-yl)piperidin-4 _- yl]N-methylcarbamate (2.1 g, (4-cyano-3-fluorophenyl)boronic acid (1.27 g, 7.7 mmol), Pd(OAc) ₂ (72 mg, 0.32 mmol), PPh ₃ ( 170 mg, 0.64 mmol), and K ₃ PO ₄ (2.0 g, 9.64 mmol) were added. The reaction mixture was kept at reflux for 16 hours under a nitrogen atmosphere. After completion, the mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was triturated with PE to give tert -butyl N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}-N-methylcarbamate (2.3 g, 87%) as a yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ): δ 1.48 (9H, s), 1.68-1.84 (4H, m), 2.72 (3H, s), 2.96-3.05 (2H, m), 4.25-4.32 (1H, m), 4.53-4.60 (2H, m), 7.69 (1H, dd, J = 6.6 Hz, 8.1 Hz), 7.84-7.90 (2H, m), 8.19 (1H, s), 8.29 (1H, s). Calcd [M+H] for C ₂₂ H ₂₆ FN ₅ O ₂ , 412; found value, 412.

Preparation 50C . tert-Butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl-N-methyl}carbamate

tert -Butyl-N-{1-[6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperidin-4-yl}-N-methylcarbamate in ACN (25 mL) (2.3 g, 5.6 mmol) was added NBS (1.0 g, 5.6 mmol) in ACN (5 mL) dropwise. The mixture was stirred for 2 hours at ambient temperature. After completion, the reaction mixture was extracted with ethyl acetate (3*100 mL) and the organic layer was washed successively with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with PE/MTBE (5:1) to yield crude tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl-N-methyl}carbamate (2.0 g, 73% yield) was obtained as a yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ): δ 1.47 (9H, s), 1.63-1.81 (4H, m), 2.72 (3H, s), 2.94-3.01 (2H, m), 4.23-4.28 (1H, m), 4.41–4.45 (2H, m), 7.64 (1H, d, J = 10.0 Hz), 7.69–7.71 (2H, m), 7.94 (1H, s). Calcd [M+H] for C ₂₂ H ₂₅ BrFN ₇ O ₂ , 490; found value, 490.

Example 50 . 2-fluoro-4-[3-(2-methyl-2H-indazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzonitrile

tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl]piperi in ACN/H 2 O ( ₃ :1, 80 mL) To a round bottom flask charged with din-4-yl}-N-methylcarbamate (1 g, 2.04 mmol), (2-methyl-2H-indazol-5-yl)boronic acid (0.54 g, 3.06 mmol), Pd (OAc) ₂ (23 mg, 0.10 mmol), S-PHOS (84 mg, 0.20 mmol) and K ₃ PO ₄ (0.86 g, 4.0 mmol) were added. The mixture was kept under reflux for 16 hours under a nitrogen atmosphere. After completion, the reaction mixture was poured into ice water and filtered. The filter cake was dissolved in ethyl acetate, washed successively with brine, dried over Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by column chromatography (50-100% ethyl acetate in PE gradient) and prep-HPLC to give a yellow solid. After the solid was suspended in ethyl acetate, HCl (6 mL, 10 M HCl-ethyl acetate) was added and stirred at ambient temperature for 2 hours. After completion, the reaction was concentrated in vacuo to give the title compound as an HCl salt (0.25 g, 27%). ¹ H NMR (300 MHz, CD ₃ OD): δ 1.77-1.81 (2H, m), 2.30-2.34 (2H, m), 2.78 (3H, s), 3.20-3.28 (2H, m), 3.31-3.33 (1H, m), 4.37 (3H, s), 4.72-4.77 (2H, m), 7.37 (1H, d, J = 6.9 Hz), 7.49-7.54 (2H, m), 7.63-7.72 (2H, m) ), 8.01 (1H, s), 8.52 (1H, s), 8.70 (1H, s). Calculated [M+H] for C ₂₅ H ₂₄ FN ₇ , 442; found value, 442.

Example 51 . 4-[6-(4-aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] It was prepared in 48% yield starting from piperidin-4-yl}carbamate and (1-methyl-1H-indazol-5-yl)boronic acid. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.64-1.67 (2H, m), 2.09-2.11 (2H, m), 3.11-3.17 (2H, m), 3.41-3.44 (1H, m), 3.99 (3H, s), 4.58-4.62 (2H, m), 7.20-7.26 (2H, m), 7.39 (1H, d, J = 6.8 Hz), 7.48-7.54 (2H, m), 7.77 (1H, s) ), 7.97 (1H, s), 8.38 (1H, s). Calculated [M+H] for C ₂₄ H ₂₂ FN ₇ , 428; found value, 428.

Example 52 . 4-[6-(4-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-6-yl)pyrazin-2-yl]-2-fluorobenzonitrile

The HCl salt of the title compound was prepared according to the procedure for the preparation of Example 49 by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] It was prepared using piperidin-4-yl}carbamate and (2-methyl-2H-indazol-6-yl)boronic acid in 33% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.69-1.79 (2H, m), 2.19-2.23 (2H, m), 3.18-3.26 (2H, m), 3.50-3.53 (1H, m), 4.34 (3H, s), 4.71-4.74 (2H, m), 7.25-7.30 (1H, m), 7.38-7.40 (1H, m), 7.50-7.53 (1H, m), 7.64-7.75 (2H, m) , 7.84–7.90 (1H, m), 8.49 (1H, d, J = 8.4 Hz), 8.66 (1H, s). Calculated [M+H] for C ₂₄ H ₂₂ FN ₇ , 428; found value, 428.

Example 53 . 4-[6-(4-aminopiperidin-1-yl)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)pyrazin-2-yl]-2- Fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] It was prepared in 39% yield using piperidin-4-yl}carbamate and (1-methylbenzotriazol-5-yl)boronic acid. ¹ H NMR (300 MHz, CD ₃ OD): δ 1.63-1.76 (2H, m), 2.14-2.19 (2H, m), 3.12-3.20 (2H, m), 3.45-3.50 (1H, m), 4.34 (3H, s), 4.66-4.71 (2H, m), 7.30 (1H, dd, J = 1.5 Hz, 8.1 Hz), 7.48 (1H, dd, J = 1.5 Hz, 10.2 Hz), 7.53 (1H, dd , J = 1.5 Hz, 8.7 Hz), 7.60 (1H, dd, J = 6.6 Hz, 8.1 Hz), 7.73 (1H, d, J = 8.7 Hz), 7.96 (1H, s), 8.44 (1H, s) . Calculated [M+H] for C ₂₃ H ₂₁ FN ₈ , 429; found value, 429.

Example 54 . 4-[6-(4-aminopiperidin-1-yl)-3-{3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl}pyrazine -2-yl] -2-fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 4,4,5,5-tetramethyl-2-(3-methyl(1,2,3-triazolino[5,4-b]pyridin-6-yl )) -1,3,2-dioxaborolane was prepared in 8% yield. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 1.56-1.65 (2H, m), 2.05-2.08 (2H, m), 3.07-3.14 (2H, m), 3.37-3.39 (1H, m), 4.30 (3H, s), 4.54-4.57 (2H, m), 7.31-7.33 (1H, d, J = 8.4 Hz), 7.67 (1H, d, J = 10.0 Hz), 7.80-7.84 (1H, m) , 8.30 (3H, br), 8.40 (1H, s), 8.61 (1H, s), 8.66 (1H, s). Calculated [M+H] for C ₂₂ H ₂₀ FN ₉ , 430; found value, 430.

Example 55 . 4-[6-(4-aminopiperidin-1-yl)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}pyrazin-2-yl]-2 -Fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 4,4,5,5-tetramethyl-2-(1-methylpyrrolo[2,3-b]pyridin-5-yl)-1,3,2- It was prepared in 53% yield using dioxaborolane. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.71-1.74 (2H, m), 2.19-2.22 (2H, m), 3.16-3.22 (2H, m), 3.50-3.54 (1H, m), 4.03 (3H, s), 4.71–4.74 (2H, m), 6.81 (1H, s), 7.39 (1H, d, J = 8.0 Hz), 7.61 (1H, d, J = 10.0 Hz), 7.67–7.71 ( 2H, m), 8.41 (1H, s), 8.50-8.52 (2H, m). Calculated [M+H] for C ₂₄ H ₂₂ FN ₇ , 428; found value, 428.

Example 56 . 2-fluoro-4-{6-[4-(methylamino)piperidyl]-3-(1-methylbenzotriazol-5-yl)pyrazin-2-yl}benzenecarbonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- It was prepared using 2-yl](4-piperidyl)}-N-methylcarboxamide and (1-methylbenzotriazol-5-yl)boronic acid in 80% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.68-1.78 (2H, m), 2.25-2.30 (2H, m), 2.77 (3H, s), 3.16-3.23 (2H, m), 3.42-3.49 (1H, m), 4.37 (3H, s), 4.72-4.86 (2H, m), 7.31 (1H, d, J = 8.0 Hz), 7.50 (1H, d, J = 10.4 Hz), 7.53 (1H, d, J = 8.8 Hz), 7.62 (1H, dd, J = 6.8 Hz, 8.0 Hz), 7.79 (1H, d, J = 8.8 Hz), 8.05 (1H, s), 8.50 (1H, s). Calculated [M+H] for C ₂₄ H ₂₃ FN ₈ , 443; found value, 443.

Example 57 . 4-{3-[6-(dimethylamino)(3-pyridyl)]-6-[4-(methylamino)piperidyl]pyrazin-2-yl}-2-fluorobenzenecarbonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- Prepared using 2-yl](4-piperidyl)}-N-methylcarboxamide and (6-dimethylamino-pyridin-3-yl)boronic acid in 77% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.61-1.72 (2H, m), 2.22-2.27 (2H, m), 2.76 (3H, s), 3.08-3.15 (2H, m), 3.30 (6H) , s), 3.36-3.45 (1H, m), 4.68-4.73 (2H, m), 7.17 (1H, dd, J = 9.2 Hz, 1.6 Hz), 7.47 (1H, dd, J = 1.2 Hz, 8.0 Hz) ), 7.61 (1H, dd, J = 1.2 Hz, 10.4 Hz), 7.78 (1H, dd, J = 6.8 Hz, 8.0 Hz), 7.84-7.87 (1H, m), 7.87 (1H, s), 8.45 ( 1H, s). Calculated [M+H] for C ₂₄ H ₂₆ FN ₇ , 432; found value, 432.

Example 58 . 4-{3-[2-(dimethylamino)pyrimidin-5-yl]-6-[4-(methylamino)piperidyl] pyrazin-2-yl}-2-fluorobenzenecarbonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and dimethyl-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolane-2 It was prepared in 59% yield using -yl)-pyrimidin-2-yl]-amine. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.61-1.71 (2H, m), 2.22-2.27 (2H, m), 2.76 (3H, s), 3.30 (6H, s), 3.08-3.14 (2H , m), 3.36-3.44 (1H, m), 4.67-4.73 (2H, m), 7.50 (1H, dd, J = 1.2 Hz, 8.0 Hz), 7.64 (1H, dd, J = 1.2 Hz, 10.4 Hz) ), 7.78 (1H, dd, J = 6.8 Hz, 8.0 Hz), 8.42 (2H, s), 8.46 (1H, s). Calculated [M+H] for C ₂₃ H ₂₅ FN ₈ , 433; found value, 433.

Example 59 . 2-fluoro-4-{6-[4-(methylamino)piperidyl]-3-(1-methylpyrazolo[5,4-b]pyridin-5-yl)pyrazin-2-yl}benzene carbonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 4,4,5,5-tetramethyl-2-(1-methylpyrazolo[5,4-b]pyridine-5- It was prepared in 91% yield using 1) -1,3,2-dioxaborolane. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.67-1.71 (2H, m), 2.25-2.28 (2H, m), 2.79 (3H, s), 3.10-3.14 (2H, m), 3.42-3.44 (1H, m), 4.12 (3H, s), 4.71-4.75 (2H, m), 7.30 (1H, dd, J = 1.6 Hz, 8.0 Hz), 7.54 (1H, dd, J = 1.2 Hz, 10.4 Hz) ), 7.63 (1H, dd, J = 0.8 Hz, 6.8 Hz), 8.08 (1H, s), 8.21 (1H, s), 8.47 (1H, s), 8.48 (s, 1H). Calculated [M+H] for C ₂₄ H ₂₃ FN ₈ , 443; found value, 443.

Example 60 . 4-{6-[4-(dimethylamino)piperidyl]-3-(2-methyl(2H-indazol-5-yl))pyrazin-2-yl}-2-fluorobenzenecarbonitrile

The HCl salt of the title compound was prepared according to the procedure for the preparation of Example 49 as 4-{6-[4-(dimethylamino)piperidyl]-3-bromopyrazin-2-yl}-2-fluorobenzenecarbo It was prepared using nitrile and (2-methyl-2H-indazol-5-yl)boronic acid in 13% yield. ¹ H NMR (400 MHz, CD ₃ OD): δ 1.79-1.83 (2H, m), 2.22-2.25 (2H, m), 2.94 (6H, s), 3.08-3.14 (2H, m), 3.57-3.58 (1H, m), 4.23 (3H, s), 4.77-4.81 (2H, m), 7.28 (1H, dd, J = 1.6 Hz, 9.2 Hz), 7.34 (1H, dd, J = 1.2 Hz, 8.0 Hz) ), 7.52 (1H, dd, J = 1.2 Hz, 10.4 Hz), 7.57–7.63 (2H, m), 7.69 (1H, s), 8.21 (1H, s), 8.42 (1H, s). Calculated [M+H] for C ₂₆ H ₂₆ FN ₇ , 456; found value, 456.

Example 61 . 2-fluoro-4-[3-(6-fluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl ]benzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 6-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-di It was prepared in 53% yield using oxabololan-2-yl) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.51 - 1.66 (m, 2 H), 2.07 - 2.24 (m, 2 H), 2.59 (s, 3 H), 2.99 - 3.15 (m, 2 H) ), 3.95 (s, 3 H), 4.57 - 4.69 (m, 2 H), 7.26 - 7.36 (m, 1 H), 7.53 - 7.61 (m, 1 H), 7.63 - 7.76 (m, 1 H), 7.77 - 7.87 (m, 1 H), 7.92 - 8.02 (m, 1 H), 8.49 - 8.64 (m, 1 H), 8.80 - 8.95 (m, 2 H), 9.02 - 9.17 (m, 1 H). Calculated [M+H] for C ₂₅ H ₂₃ F _-2 N ₇ , 460; found value, 460.

Example 62 . 4-[3-(6,7-difluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]- 2-Fluorobenzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3, It was prepared in 37% yield using 2-dioxaborolan-2-yl) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.46 - 1.70 (m, 2 H), 1.99 - 2.25 (m, 2 H), 2.59 (s, 3 H), 2.95 - 3.16 (m, 2 H) ), 3.26 - 3.54 (m, 2 H), 4.00 (s, 3 H), 4.51 - 4.69 (m, 2 H), 7.21 - 7.38 (m, 1 H), 7.42 - 7.66 (m, 2 H), 7.77 - 7.86 (m, 1 H), 8.22 - 8.44 (s, 1 H), 8.54 - 8.64 (s, 1 H), 8.72 - 8.88 (m, 2 H). Calculated [M+H] for C ₂₅ H ₂₂ F _-3 N ₇ , 478; found, 478.

Example 63 . 2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- Prepared using 2-yl](4-piperidyl)}-N-methylcarboxamide and (3-fluoro-4-methoxyphenyl)boronic acid in 94% yield. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.46 - 1.70 (m, 2 H), 1.99 - 2.25 (m, 2 H), 2.55 - 2.64 (m, 3 H), 2.95 - 3.16 (m, 2 H), 3.26 - 3.54(m, 2 H), 4.00(s, 3 H), 4.51 - 4.69(m, 2 H), 7.21 - 7.38(m, 1 H), 7.42 - 7.66(m, 2 H) ), 7.77 - 7.86 (m, 1 H), 8.22 - 8.44 (m, 1 H), 8.54 - 8.64 (m, 1 H), 8.72 - 8.88 (m, 2 H). Calcd [M+H] for C ₂₄ H ₂₃ F _-2 N ₅ O, 436; found value, 436.

Example 64 . 2-fluoro-4-[3-[2-(1-hydroxycyclopentyl)ethynyl]-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzonitrile

4-{3-bromo-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl}-2-fluorobenzo It was prepared in 25% yield using nitrile and 1-ethynylcyclopentan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.36 - 1.56 (m, 2 H), 1.69 - 1.82 (m, 2 H), 1.82 - 1.92 (m, 2 H), 2.03 - 2.12 (m, 2 H) ), 2.43 - 2.57 (m, 6 H), 2.66 - 2.80 (m, 1 H), 2.85 - 3.00 (m, 2 H), 3.05 - 3.24 (m, 2 H), 4.29 - 4.45 (m, 2 H) ), 7.18 - 7.34 (m, 1 H), 7.57 - 7.78 (m, 1 H), 7.90 - 8.05 (m, 2 H), 8.09 - 8.20 (m, 1 H). Calcd [M+H] for C ₂₄ H ₂₆ FN ₅ O, 420; found value, 420.

Example 65 . 2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-methylbenzimidazol-5-yl)pyrazin-2-yl]benzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3, It was prepared in 48% yield using 2-dioxaborolan-2-yl) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.50 - 1.77 (m, 2 H), 2.11 - 2.21 (m, 2 H), 2.56 (br. s., 3 H), 2.95 - 3.12 (m , 2 H), 3.24 - 3.39 (m, 1 H), 3.43 - 3.82 (m, 1 H), 4.05 (s, 3 H), 4.56 - 4.65 (m, 2 H), 7.17 - 7.38 (m, 1 H), 7.41 - 7.54(m, 1 H), 7.56 - 7.71(m, 1 H), 7.78 - 7.90(m, 3 H), 8.52 - 8.64(m, 1 H), 9.06 - 9.25(br, 2 H), 9.49 - 9.59 (s, 1 H). Calculated [M+H] for C ₂₅ H ₂₄ F _- N ₇ , 442; found value, 442.

Example 66 . 2-Fluoro-4-[3-(3-hydroxy-3-methylbut-1-ynyl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzo nitrile

4-{3-bromo-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl}-2-fluorobenzo It was prepared in 34% yield using nitrile and 2-methylbut-3-yn-2-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 1.39 - 1.50 (m, 2 H), 1.98 - 2.13 (m, 2 H), 2.17 - 2.39 (m, 3 H), 2.50 (s, 3 H), 2.71 - 2.80 (m, 1 H), 2.88 (s, 3 H), 2.96 (s, 3 H), 3.07 - 3.19 (m, 2 H), 4.26 - 4.46 (m, 2 H), 7.16 - 7.38 ( m, 1 H), 7.57 - 7.76 (m, 1 H), 7.89 - 8.08 (m, 3 H), 8.10 - 8.22 (m, 1 H). Calcd [M+H] for C ₂₂ H ₂₄ FN ₅ O, 394; found value, 394.

Example 67 . 2-fluoro-4-[3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazine -2-yl] benzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 6-fluoro-1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1 It was prepared in 46% yield using ,3,2-dioxaborolan-2-yl)-1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.58 (d, J =6.57 Hz, 8 H), 2.09 - 2.24 (m, 2 H), 2.56 (br. s., 3 H), 2.98 - 3.14 (m, 2 H), 3.25 - 3.37 (m, 1 H), 3.41 - 3.80 (m, 1 H), 4.51 - 4.71 (m, 3 H), 4.79 - 5.06 (m, 2 H), 7.28 - 7.44 (m, 1 H), 7.53 - 7.64 (m, 1 H), 7.77 - 7.95 (m, 2 H), 7.95 - 8.07 (m, 1 H), 8.54 - 8.67 (m, 1 H), 8.99 - 9.27 (m, 2 H), 9.46 - 9.65 (m, 1 H). Calculated [M+H] for C ₂₇ H ₂₇ F _-2 N ₇ , 488; found, 488.

Example 68 . 2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2- It was prepared in 49% yield using dioxaborolan-2-yl) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, methanol- d ₄ ) δ ppm 2.07 - 2.26 (m, 2 H), 2.56 - 2.63 (m, 3 H), 2.98 - 3.10 (m, 2 H), 3.64 - 3.78 (m, 9 H), 4.53 - 4.69(m, 2 H), 4.92 - 5.11(m, 1 H), 7.29 - 7.36(m, 1 H), 7.42 - 7.49(m, 1 H), 7.60 - 7.69(m, 2 H), 7.83 - 7.97 (m, 2 H), 8.52 - 8.66 (m, 1 H), 9.36 - 9.56 (m, 1 H). Calculated [M+H] for C ₂₇ H ₂₈ F _- N ₇ , 470; found value, 470.

Example 69 . 4-[3-(1-ethyl-6-fluorobenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]-2-fluoro Robenzonitrile

( tert -butoxy)-N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazine- 2-yl](4-piperidyl)}-N-methylcarboxamide and 1-ethyl-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-di It was prepared in 45% yield using oxabololan-2-yl) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.49 (m, 3 H), 1.55 - 1.71 (m, 2 H), 2.10 - 2.23 (m, 2 H), 2.58 (s, 3 H), 2.95 - 3.13 (m, 2 H), 3.27 - 3.40 (m, 1 H), 3.44 - 3.54 (m, 2 H), 3.65 - 3.76 (m, 2 H), 4.36 - 4.47 (m, 2 H), 4.55 - 4.68 (m, 2 H), 7.22 - 7.40 (m, 1 H), 7.56 - 7.69 (m, 1 H), 7.84 - 7.95 (m, 2 H), 8.03 (br. s., 1 H) , 8.61 (s., 1 H), 9.11 (br. s., 2 H), 9.46 (br. s., 1 H). Calculated [M+H] for C ₂₆ H ₂₅ F _-2 N ₇ , 474; found value, 474.

Example 70 . 4-[6-(4-aminopiperidin-1-yl)-3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2- Fluorobenzonitrile

The HCl salt of the title compound was prepared according to the procedure for the preparation of Example 49 by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 6-fluoro-1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane It was prepared in 45% yield using -2-yl)-1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.601.46-1.74 (m, 10 H), 1.97 - 2.16 (m, 2 H), 3.00 - 3.17 (m, 2 H), 3.57 (s, 3 H), 3.60-3.75(m, 2 H), 4.48 - 4.67(m, 2 H), 4.85 - 5.03(m, 1 H), 7.25 - 7.42(m, 1 H), 7.54 - 7.67(m, 1 H), 7.76 - 7.97 (m, 2 H), 7.97 - 8.06 (m, 1 H), 8.56 - 8.64 (s, 1 H), 9.46 - 9.61 (m, 1 H). Calculated [M+H] for C ₂₆ H ₂₅ F _-2 N ₇ , 474; found value, 474.

Example 71 . 4-[6-(4-aminopiperidin-1-yl)-3-(1-ethyl-6-fluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 1-ethyl-6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- It was prepared in 60% yield using 1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.40 - 1.55 (m, 3 H), 1.55 - 1.70 (m, 2 H), 1.97 - 2.15 (m, 2 H), 3.01 - 3.23 (m, 3 H), 3.66 - 3.76(m, 2 H), 4.35 - 4.50(m, 2 H), 4.51 - 4.65(m, 2 H), 7.30 - 7.41(m, 1 H), 7.52 - 7.67(m, 1 H), 7.78 - 7.94 (m, 2 H), 8.00 - 8.09 (m, 1 H), 8.16 - 8.33 (m, 1 H), 8.59 (br. s., 1 H), 9.52 (br. s ., 1 H). Calculated [M+H] for C ₂₅ H ₂₃ F _-2 N ₇ , 460; found value, 460.

Example 72 . 4-[6-(4-aminopiperidin-1-yl)-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 1-(propan-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) It was prepared in 42% yield using -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.45-1.68 (m, 2 H), 1.60 (d, J =6.82 Hz, 6 H), 1.97 - 2.09 (m, 2 H), 3.02 - 3.17 (m, 2 H), 3.44 - 3.52 (m, 2 H), 3.65 - 3.81 (m, 1 H), 4.47 - 4.71 (m, 2 H), 4.87 - 5.07 (m, 1 H), 7.22 - 7.35 (m, 1 H), 7.42 - 7.53 (m, 1 H), 7.56 - 7.68 (m, 1 H), 7.69 - 7.80 (m, 1 H), 7.80 - 7.89 (m, 1 H), 7.89 - 7.97 (m, 1 H), 8.50 - 8.64 (m, 1 H), 9.40 - 9.54 (m, 1 H). Calculated [M+H] for C ₂₆ H ₂₆ F _- N ₇ , 456; found value, 456.

Example 73 . 4-[6-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] -2-Fluorobenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- It was prepared in 40% yield using 1) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.47-1.62 (m, 2 H), 1.56 (d, J =6.57 Hz, 6H), 1.97 - 2.10 (m, 2 H), 2.99 - 3.17 ( m, 2 H), 3.45 - 3.53 (m, 2 H), 3.61 - 3.76 (m, 2 H), 4.47 - 4.66 (m, 2 H), 4.75 - 5.01 (m, 1 H), 7.18 - 7.38 ( m, 1 H), 7.52 - 7.68 (m, 2 H), 7.77 - 7.89 (m, 1 H), 7.89 - 8.03 (m, 1 H), 8.42 - 8.69 (m, 2 H). Calculated [M+H] for C ₂₆ H ₂₄ F ₃ N ₇ , 492; found value, 492.

Example 74 . 4-[6-(4-aminopiperidin-1-yl)-3-(1-ethyl-6,7-difluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro Robenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 1-ethyl-6,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- It was prepared in 64% yield using 1) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.49 - 1.58 (m, 3 H), 1.58 - 1.73 (m, 2 H), 1.98 - 2.18 (m, 2 H), 2.97 - 3.19 (m, 2 H), 3.54 - 3.66(m, 1 H), 3.66 - 3.76(m, 2 H), 4.43 - 4.68(m, 4 H), 7.22 - 7.38(m, 1 H), 7.58 - 7.71(m, 1 H), 7.74 - 7.91 (m, 2 H), 8.57 - 8.65 (m, 1 H), 9.57 (br. s., 1 H). Calculated [M+H] for C ₂₅ H ₂₂ F ₃ N ₇ , 478; found, 478.

Example 75 . 4-[6-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1-methylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro Robenzonitrile

Following the procedure for the preparation of Example 49, the HCl salt of the title compound was prepared by tert -butyl N-{1-[5-bromo-6-(4-cyano-3-fluorophenyl)pyrazin-2-yl] Piperidin-4-yl}carbamate and 6,7-difluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- It was prepared in 51% yield using 1) -1H-1,3-benzodiazole. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.51 - 1.68 (m, 2 H), 1.93 - 2.10 (m, 2 H), 2.96 - 3.18 (m, 2 H), 3.62 - 3.75 (m, 4 H), 4.00(s(, 3 H), 4.47 - 4.62(m, 2 H), 7.22 - 7.35(m, 1 H), 7.43 - 7.65(m, 2 H), 7.75- 7.78(m, 1 H), 8.01-8.21 (m, 2 H), 8.40 (s, 1 H), 8.61 (s, 1 H) Calculated [M+H] for C ₂₄ H ₂₀ F ₃ N ₇ , 464; found value, 464.

II. biological evaluation

Example 1a : In vitro enzyme inhibition assay - LSD-1

This assay measures the ability of a test compound to inhibit LSD1 demethylase activity. Full-length human LSD1 expressed by E. coli (accession number 060341) was purchased from Active Motif (Cat# 31334).

Enzymatic assays of LSD1 activity are based on Time Resolved-Fluorescence Resonance Energy Transfer (TR-FRET) detection. The inhibitory properties of the compounds against LSD1 were determined in a 384-well plate format under the following reaction conditions: 0.1-0.5 nM LSD1, 50 nM H3K4me1-biotin-labeled peptide (Anaspec cat# 64355) in 50 mM HEPES, pH 7.3 assay buffer, 2 μM FAD, 10 mM NaCl, 0.005% Brij35, 0.5 mM TCEP, 0.2 mg/mL BSA. Detection reagent phycolink streptavidin-allophycocyanin (Phycolink Streptavidin-allophycocyanin) (Prozyme) and a native anti-unmodified histone H3 lysine 4 (H3K4) antibody (PerkinElmer) were added to final concentrations of 12.5 nM and 0.25 nM, respectively, and the reaction product was then treated with TR- Quantitatively measured by FRET.

The assay reaction was performed according to the following procedure: A mixture of 2 μl of 11 point serially diluted test compound in 3% DMSO and 2 μl of 150 nM H3K4me1-biotin-labeled peptide was added to each well of the plate, followed by 2 μl of 0.3 nM LSD1. and FAD 6 μM was added to initiate the reaction. The reaction mixture was then incubated for 1 hour at room temperature and 1.8 mM 2-PCPA in LANCE detection buffer containing 25 nM Pycolink streptavidin-allophycocyanin and 0.5 nM Europum anti-unmodified H3K4 antibody. 6 μl was added to terminate. After 1 hour incubation at room temperature, the plate was read on an EnVision Multilabel Reader in TR-FRET mode (excitation at 320 nm, emission at 615 nm and 665 nm). For each well, the ratio was calculated (665/615) and fit to determine the inhibition constant (IC ₅₀ ).

The ability of the compounds described herein to inhibit LSD1 activity was quantified, and the respective IC ₅₀ values were determined. Table 3 provides IC ₅₀ values for various substituted heterocyclic compounds described herein.

[Table 3]

Note: Biochemical assay IC ₅₀ data are assigned to the following ranges:

A: ≤ 100 nM

B: > 100 nM to ≤ 1,000 nM

C: > 1,000 nM to ≤ 10,000 nM

D: > 10,000 nM

Example 2 : In vitro enzyme inhibition assay - MAO selectivity

Human recombinant monoamine oxidase proteins MAO-A and MAO-B are obtained. MAOs catalyze the oxidative deamination of primary, secondary and tertiary amines. To monitor MAO enzymatic activity and/or their rate of inhibition by the inhibitor(s) of interest, a fluorescence-based (inhibitor)-screening assay is performed. 3-(2-aminophenyl)-3-oxopropanamine (kyneuramine dihydrobromide, Sigma Aldrich), a non-fluorescent compound, is selected as substrate. Kyneuramine is a nonspecific substrate for both MAO activities. Upon undergoing oxidative deamination by MAO activity, kynuramine is converted to the resulting fluorescent product, 4-hydroxyquinoline (4-HQ).

Monoamine oxidase activity is estimated by measuring the conversion of kyneuramine to 4-hydroxyquinoline. Assays are performed in 96 well black plates (Corning) with clear bottoms in a final volume of 100 μl. Assay buffer is 100 mM HEPES, pH 7.5. Each experiment is performed in triplicate with the same experiment.

Briefly, fixed amounts of MAO (0.25 μg for MAO-A and 0.5 μg for AO-B) were added in reaction buffer for 15 min on ice at various concentrations of compounds as described herein (e.g., inhibitors). in the absence and/or presence of 0-50 μM, depending on the strength. Tranilcypromine (Biomol International) is used as a control for inhibition.

After release of the enzyme(s) interacting with the test compound, 60 to 90 μM of kynuramine was added to each reaction for the MAO-B and MAO-A assays, respectively, and the reaction was incubated for 1 hour at 37° C. in the dark. put Oxidative deamination of the substrate is stopped by the addition of 50 μl of 2N NaOH. The conversion of kyneuramine to 4-hydroxyquinoline is monitored by fluorescence (excitation at 320 nm, emission at 360 nm) using a microplate reader (Infinite 200, Tecan). Arbitrary units are used to determine the level of fluorescence produced in the absence and/or presence of the test compound.

Maximal oxidative deamination activity is obtained by measuring 4-hydroxyquinoline formed from kyneuramine deamination in the absence of test compound, corrected for background fluorescence. The Ki (IC ₅₀ ) of each inhibitor is determined at Vmax/2.

Example 3: LSD1 CD11b cell assay

To analyze LSD1 inhibitor potency in cells, CD11b flow cytometric analysis was performed. LSD1 inhibition induces CD11b expression in THP-1 (AML) cells, which can be measured by flow cytometry. THP-1 cells were seeded at 100,000 cells/well in RPMI 1640 medium containing 10% fetal bovine serum in 24 well plates with a final volume of 500 μl per well. LSD1 test compounds were serially diluted in DMSO. Dilutions were added to each well according to a final concentration of 0.2% DMSO. Cells were cultured at 37° C. under 5% CO ₂ for 4 days. 250 μl of each well was transferred to a well of a 96 well round bottom plate. Plates were centrifuged at 1200 rpm at 4° C. in a Beckman Coulter Alegra 6KR centrifuge for 5 minutes. The medium was removed leaving the cells at the bottom of the well. The cells were washed in 100 μl of cold Hank's Balanced Salt Soultion (HBSS) + 2% Bovine Serum Albumin (BSA) solution, and centrifuged at 1200 rpm at 4° C. for 5 minutes. Wash solution was removed. Cells were resuspended in 100 μl HBSS combined with 2% BSA containing a 1:15 dilution of APC conjugated mouse anti-CD11b antibody (BD Pharmingen Cat# 555751) and incubated on ice for 25 minutes . Cells were centrifuged and washed twice in 100 μl HBSS + 2% BSA. After the final spin, cells were resuspended in 100 μl HBSS + 2% BSA containing 1 ug/mL DAPI (4′,6-diamidino-2-phenylindole). Cells were then analyzed by flow cytometry on a BD FACSAria machine. Cells were analyzed for CD11b expression. The percentage of CD11b expressing cells for each inhibitor concentration was used to determine an IC ₅₀ curve for each compound analyzed.

Table 4 provides the cellular IC ₅₀ values of various substituted heterocyclic compounds described herein.

[Table 4]

Note: Assay IC ₅₀ data are assigned to the following ranges:

A: ≤ 0.10 μM C: > 1.0 μM to ≤ 10 μM

B: > 0.10 μM to ≤ 1.0 μM D: > 10 μM

Example 4: In Vivo Xenograph Study - MCF-7 Xenograph

Sustained release pellets containing 0.72 mg of 17-β estradiol are subcutaneously implanted into nu/nu mice. MCF-7 cells are grown at 37° C. in 5% CO ₂ in RPMI with 10% FBS. Cells are spun down and resuspended at 1×10 ⁷ cells/ml in 50% RPMI (serum free) and 50% Matrigel. MCF-7 cells are injected subcutaneously into the right flank 2-3 days after pellet implantation (100 μl/animal), and tumor volume (length×width ^2/2 ) is monitored biweekly. When tumors reach an average volume of ˜200 mm ³ , animals are randomized and treatment begins. Animals are treated with vehicle or compound daily for 4 weeks. Tumor volume and body weight are monitored biweekly throughout the study. At the end of the treatment period, plasma and tumor samples are taken for pharmacokinetic and pharmacodynamic analysis, respectively.

Example 5: In Vivo Genograph Study - LNCaP Genograph

LNCaP cells with stable knockdown of LSDl (shLSDl cells) or control cells (e.g. shNTC cells) are inoculated by subcutaneous injection into the dorsal flank of nude mice (e.g. 100 μl of 50% RPMI 1640/BD Matrigel). 3×10 ⁶ cells in medium). Mouse body weight and tumor size are measured once per week, and tumor volume is estimated using the formula (7i/6)(L×W), where L is the tumor length and W is the tumor width. A two-sample t-test is performed to determine statistical differences in mean tumor volume between the two groups.

Unmodified LNCaP cells are inoculated by subcutaneous injection into the dorsal flank of nude mice (eg, 3×10 ⁶ cells in 100 μl of 50% RPMI 1640/BD Matrigel). After 3 weeks, mice were injected with water (control), pargyline (0.53 mg or 1.59 mg; final concentration 1 or 3 mM, assuming 70% bioavailability), or XB154 (4 or 20 μg; final concentration 1 or 5 μM, 70 μM). % bioavailability (assuming) by intraperitoneal injection once per day, or treatment with the test compound (5 mg/kg weekly or 10 mg/kg weekly). Treatment continues for 3 weeks, during which time mouse weight and tumor volume are measured as above.

shLSDl LNCaP cells or control cells are injected into nude mice as above. After 3 weeks, mice were treated with mitomycin C 2.6 μg (expected final concentration 1 μM, assuming 40% bioavailability), olaparib (e.g., about 0.5 mg/kg to 25 mg/kg), or vehicle for 3 weeks. Administer intraperitoneally once daily. In another embodiment, unmodified LNCaP cells are injected into nude mice as above.

After 3 weeks, mice are treated with the test compound, or vehicle, with MMC or olaparib, as above. Treatment continues for 3 weeks, during which time mouse weight and tumor volume are measured as above.

The reduction in tumor volume in mice injected with shLSDl cells compared to controls indicates that LSDl inhibition reduces tumor growth in vivo.

Similarly, a decrease in tumor volume compared to controls in mice injected with LNCaP cells and treated with the compounds described herein indicates that LSD1 inhibition reduces tumor growth in vivo. Finally, the reduction in tumor volume in mice injected with LNCaP cells and treated with the compound described herein plus olaparib, compared to mice treated with the compound described herein alone, showed that inhibition of LSDl+inhibition of PARP in vivo tumor indicates a decrease in growth.

Harvested xenograft tissue is tested for evidence of LSD1 inhibition. This is evaluated by Western blot to examine the overall level of 2MK4 and 2MK9 histone marks, the expression of the FA/BRCA gene, FANCD2 ubiquitination, and, in the case of shRNA cells, the LSD1 protein level. A decrease in one or more of these parameters indicates effective inhibition of LSD 1. Additionally, the effect on DNA damage repair is assessed by staining for H2AX foci.

III. Manufacture of Pharmaceutical Formulations

Example 1 : oral tablet

A tablet is prepared by mixing 48% by weight of Formulas I, II, III, or a pharmaceutically acceptable salt thereof, 45% by weight of microcrystalline cellulose, 5% by weight of low-substituted hydroxypropyl cellulose, and 2% by weight of magnesium stearate. . Tablets are prepared by direct compression. The total weight of the compressed tablet is maintained at 250-500 mg.

Claims (53)

A compound having the structure of formula (IV) or a pharmaceutically acceptable salt thereof:

In the above formula,
X and Y are each independently selected from CH, CF, C-CH ₃ or N;
Z is -G, -CH ₂ -G, -CH ₂ -CH ₂ -G, -N(R ¹ )-G, -N(R ¹ )-CH ₂ -G or -C(O)N(R ² )(R ³ );
X ¹ , X ² and X ³ are each independently selected from N or CR ⁴ , provided that at least one of X ¹ , X ² , or X ³ is N;
G is (a) a carbocyclyl, aryl or heterocyclyl; or
(b) when X ¹ and X ³ are each N and X ² is CR ⁴ , optionally substituted with a substituent selected from the group consisting of carbocyclyl, aryl, halogen, alkyl and -N(R ² )(R ³ ); heterocyclyl, or heteroaryl
is one of;
R ¹ is hydrogen or alkyl;
R ² and R ³ are independently selected from hydrogen, alkyl, heterocyclyl, heterocyclylalkyl, or optionally, R ² and R ³ are joined to form an N-linked heterocyclyl ring system;
R ⁴ is hydrogen, halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy;
R is aryl, heteroaryl, alkynyl, or cycloalkylalkynylene. The compound according to claim 1, wherein R is aryl or heteroaryl, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein Formula IV is Formula IVa, or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1, wherein Formula IV is Formula IVb, or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1, wherein Formula IV is Formula IVc, or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1, wherein Formula IV is Formula IVd: or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1, wherein Formula IV is Formula IVe, or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1, wherein Formula IV is Formula IVf, or a pharmaceutically acceptable salt thereof:

. The compound according to claim 1, wherein Formula IV is Formula IVg, or a pharmaceutically acceptable salt thereof:

. The method of claim 1, wherein X is
(a) CH; or
(b) CF
A phosphorus compound or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein Y is
(a) CH; or
(b) CF
A phosphorus compound or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein X is C-H and Y is C-H, or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein Z is
(a) -N(R ¹ )-CH ₂ -G;
(b) -N(R ¹ )-G;
(c) -CH ₂ -G; or
(d) -G
A phosphorus compound or a pharmaceutically acceptable salt thereof. According to claim 13,
(a) R ² and R ³ are independently selected from hydrogen or alkyl, or
(b) R ² and R ³ are independently selected from heterocyclyl or heterocyclylalkyl; or
(c) A compound or a pharmaceutically acceptable salt thereof, wherein R ² and R ³ are bonded to form an N-linked heterocyclyl ring system. 14. The compound of claim 13, wherein (a) R ¹ is hydrogen; or (b) a compound wherein R ¹ is alkyl, or a pharmaceutically acceptable salt thereof. The compound of claim 1 , wherein (a) R ⁴ is hydrogen; or (b) a compound wherein R ⁴ is C ₁ -C ₃ alkoxy, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein G is heterocyclyl, or a pharmaceutically acceptable salt thereof. The compound according to claim 1, wherein G is nitrogen-containing heterocyclyl, or a pharmaceutically acceptable salt thereof. The compound according to claim 18, wherein the nitrogen-containing heterocyclyl is a 5-membered or 6-membered heterocyclyl, or a pharmaceutically acceptable salt thereof. 19. The compound or pharmaceutically acceptable salt thereof according to claim 18, wherein the heterocyclyl is selected from the formulas:

The compound according to claim 1, wherein R is heteroaryl, or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 21, wherein R is a monocyclic nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof. 22. The compound according to claim 21, wherein R is a bicyclic nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof. 24. The compound or a pharmaceutically acceptable salt thereof according to claim 23, wherein R is selected from the formulas:

The compound according to claim 1, wherein R is aryl, or a pharmaceutically acceptable salt thereof. 26. The compound according to claim 25, wherein aryl is an optionally substituted phenyl group, or a pharmaceutically acceptable salt thereof. 27. The method of claim 26, wherein the optionally substituted phenyl group is selected from 4-methylphenyl, 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, 4-(methylsulfonyl)phenyl or 4-trifluoromethylphenyl. A compound or a pharmaceutically acceptable salt thereof. 27. The compound according to claim 26, wherein the optionally substituted phenyl group is selected from 4-methoxyphenyl, 3-fluoro-4-methoxyphenyl or 3-chloro-4-methoxyphenyl, or a pharmaceutically acceptable compound thereof. salt. The compound according to claim 5, wherein X is CF, Y is CH, and R ⁴ is hydrogen, or a pharmaceutically acceptable salt thereof. 30. The compound according to claim 29, wherein R is a bicyclic nitrogen-containing heteroaryl, or a pharmaceutically acceptable salt thereof. 31. A compound or a pharmaceutically acceptable salt thereof according to claim 30, wherein R is selected from the formulas:

31. A compound or a pharmaceutically acceptable salt thereof according to claim 30, wherein R is selected from the formulas:

According to claim 29,
G is

A phosphorus compound or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the compound
4-[6-(4-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile;
2-fluoro-4-[3-(2-methyl-2H-indazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzonitrile ,
4-[6-(4-aminopiperidin-1-yl)-3-(1-methyl-1H-indazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(2-methyl-2H-indazol-6-yl)pyrazin-2-yl]-2-fluorobenzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(1-methyl-1H-1,2,3-benzotriazol-5-yl)pyrazin-2-yl]-2- fluorobenzonitrile,
4-[6-(4-aminopiperidin-1-yl)-3-{3-methyl-3H-[1,2,3]triazolo[4,5-b]pyridin-6-yl}pyrazine -2-yl] -2-fluorobenzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-{1-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl}pyrazin-2-yl]-2 -fluorobenzonitrile,
2-fluoro-4-{6-[4-(methylamino)piperidyl]-3-(1-methylbenzotriazol-5-yl)pyrazin-2-yl}benzenecarbonitrile;
4-{3-[6-(dimethylamino)(3-pyridyl)]-6-[4-(methylamino)piperidyl]pyrazin-2-yl}-2-fluorobenzenecarbonitrile;
4-{3-[2-(dimethylamino)pyrimidin-5-yl]-6-[4-(methylamino)piperidyl]pyrazin-2-yl}-2-fluorobenzenecarbonitrile;
2-fluoro-4-{6-[4-(methylamino)piperidyl]-3-(1-methylpyrazolo[5,4-b]pyridin-5-yl)pyrazin-2-yl}benzene carbonitrile,
4-{6-[4-(dimethylamino)piperidyl]-3-(2-methyl(2H-indazol-5-yl))pyrazin-2-yl}-2-fluorobenzenecarbonitrile;
2-fluoro-4-[3-(6-fluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl ]benzonitrile,
4-[3-(6,7-difluoro-1-methylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]- 2-fluorobenzonitrile;
2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile,
2-fluoro-4-[3-[2-(1-hydroxycyclopentyl)ethynyl]-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzonitrile ,
2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-methylbenzimidazol-5-yl)pyrazin-2-yl]benzonitrile;
2-fluoro-4-[3-(3-hydroxy-3-methylbut-1-ynyl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]benzo nitrile,
2-fluoro-4-[3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazine -2-yl] benzonitrile,
2-fluoro-4-[6-[4-(methylamino)piperidin-1-yl]-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] benzonitrile,
4-[3-(1-ethyl-6-fluorobenzimidazol-5-yl)-6-[4-(methylamino)piperidin-1-yl]pyrazin-2-yl]-2-fluoro robenzonitrile,
4-[6-(4-aminopiperidin-1-yl)-3-(6-fluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2- fluorobenzonitrile,
4-[6-(4-aminopiperidin-1-yl)-3-(1-ethyl-6-fluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile ,
4-[6-(4-aminopiperidin-1-yl)-3-(1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluorobenzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1-propan-2-ylbenzimidazol-5-yl)pyrazin-2-yl] -2-fluorobenzonitrile;
4-[6-(4-aminopiperidin-1-yl)-3-(1-ethyl-6,7-difluorobenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro robenzonitrile, or
4-[6-(4-aminopiperidin-1-yl)-3-(6,7-difluoro-1-methylbenzimidazol-5-yl)pyrazin-2-yl]-2-fluoro A compound that is robenzonitrile or a pharmaceutically acceptable salt thereof. The method of claim 1, wherein the compound
4-[5-(4-methylphenyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-[5-(4-fluorophenyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-[5-(4-chlorophenyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-{2-[(3a R ,6a S )-octahydropyrrolo[3,4-c]pyrrol-2-yl]-5-(4-methylphenyl)pyrimidin-4-yl}benzonitrile;
4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile;
4-{2-[(3a R ,8a S )-decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-methylphenyl)pyrimidin-4-yl}benzonitrile;
4-{2-[(3aR,8aS)-decahydropyrrolo[3,4-d]azepin-6-yl]-5-(4-fluorophenyl)pyrimidin-4-yl}benzonitrile;
4-(2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}-5-[4-(trifluoromethyl)phenyl]pyrimidin-4-yl)benzonitrile;
4-[5-(2-cyclopropylethynyl)-2-{[(3 S )-pyrrolidin-3-ylmethyl]amino}pyrimidin-4-yl]benzonitrile;
4-(2-{[(3aR,5S,6aS)-octahydrocyclopenta[c]pyrrol-5-yl]amino}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
( + )- 4-(2-{[(3-fluoropyrrolidin-3-yl)methyl]amino}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
( + )- 4-[5-(4-methylphenyl)-2-[(piperidin-3-yl)amino]pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-[(piperidin-4-yl)amino]pyrimidin-4-yl]benzonitrile;
( + )- 4-[5-(4-methylphenyl)-2-[(piperidin-3-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-[(piperidin-4-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
( + )- 4-[5-(4-methylphenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
( + )- 4-[5-(4-fluorophenyl)-2-[(morpholin-2-ylmethyl)amino]pyrimidin-4-yl]benzonitrile;
4-(2-{2,7-diazaspiro[4.4]nonan-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-(2-{2,8-diazaspiro[4.5]decan-2-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,4-c]pyridin-2-yl}pyrimidin-4-yl]benzonitrile;
4-[5-(4-methylphenyl)-2-{octahydro-1H-pyrrolo[3,2-c]pyridin-5-yl}pyrimidin-4-yl]benzonitrile;
4-(2-{2,8-diazaspiro[4.5]decan-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-(2-{1,8-diazaspiro[4.5]decan-8-yl}-5-(4-methylphenyl)pyrimidin-4-yl)benzonitrile;
4-[5-(4-methylphenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}pyrimidin-4-yl]benzonitrile; and
4-[5-(4-fluorophenyl)-2-{9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl}pyrimidin-4-yl]benzonitrile
A compound selected from or a pharmaceutically acceptable salt thereof. Inhibiting lysine-specific demethylase 1 activity by exposing the lysine-specific demethylase 1 enzyme to a compound of Formula IV according to any one of claims 1 to 35, wherein gene transcription in a cell is In vitro methods of conditioning. A pharmaceutical composition for treating cancer in a patient in need thereof, comprising a compound of Formula IV according to any one of claims 1 to 35. 38. The pharmaceutical composition according to claim 37, wherein the cancer is acute myeloid leukemia, breast cancer or prostate cancer. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete